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Ohnishi K, Sokabe T. Thermosensory Roles of G Protein-Coupled Receptors and Other Cellular Factors in Animals. Bioessays 2025; 47:e202400233. [PMID: 39723698 PMCID: PMC11848117 DOI: 10.1002/bies.202400233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/05/2024] [Accepted: 12/09/2024] [Indexed: 12/28/2024]
Abstract
In this review, we introduce the concept of "dual thermosensing mechanisms," highlighting the functional collaboration between G protein-coupled receptors (GPCRs) and transient receptor potential (TRP) channels that enable sophisticated cellular thermal responsiveness. GPCRs have been implicated in thermosensory processes, with recent findings identifying several candidates across species, including mammals, fruit flies, and nematodes. In many cases, these GPCRs work in conjunction with another class of thermosensors, TRP channels, offering insights into the complex mechanisms underlying thermosensory signaling. We examine how GPCRs function as thermosensors and how their signaling regulates cellular thermosensation, illustrating the complexity of thermosensory systems. Understanding these dual thermosensory mechanisms would advance our comprehension of cellular thermosensation and its regulatory pathways.
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Affiliation(s)
- Kohei Ohnishi
- Physiology and Biophysics, Graduate School of Biomedical and Health Sciences (Medical)Hiroshima UniversityHiroshimaJapan
| | - Takaaki Sokabe
- Section of Sensory Physiology, Center for Genetic Analysis of BehaviorNational Institute for Physiological SciencesOkazakiAichiJapan
- Thermal Biology Group, Exploratory Research Center on Life and Living SystemsNational Institutes of Natural SciencesOkazakiAichiJapan
- Graduate Institute for Advanced Studies, SOKENDAIHayamaKanagawaJapan
- AMED‐PRIMEJapan Agency for Medical Research and DevelopmentTokyoJapan
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2
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Scheuren PS, Calvo M. Exploring neuroinflammation: A key driver in neuropathic pain disorders. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2024; 179:311-338. [PMID: 39580216 DOI: 10.1016/bs.irn.2024.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2024]
Abstract
Inflammation is a fundamental part of the body's natural defense mechanism, involving immune cells and inflammatory mediators to promote healing and protect against harm. In the event of a lesion or disease of the somatosensory nervous system, inflammation, however, triggers a cascade of changes in both the peripheral and central nervous systems, ultimately contributing to chronic neuropathic pain. Substantial evidence links neuroinflammation to various conditions associated with neuropathic pain. This chapter will explore the role of neuroinflammation in the initiation, maintenance, and resolution of peripheral and central neuropathic pain. Additionally, biomarkers of neuroinflammation in humans will be examined, emphasizing their relevance in different neuropathic pain disorders.
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Affiliation(s)
- Paulina S Scheuren
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
| | - Margarita Calvo
- Physiology Department, Pontificia Universidad Católica de Chile, Santiago, Chile; Millennium Nucleus for the Study of Pain (MiNuSPain), Santiago, Chile
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3
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Yang C, Wei C, Alam S, Chen X, McKemy DD. The neurotrophic factor artemin and its receptor GFRα3 mediate migraine-like pain via the ion channel TRPM8. Cephalalgia 2024; 44:3331024241297679. [PMID: 39552306 DOI: 10.1177/03331024241297679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
BACKGROUND Migraine has a strong genetic foundation, including both monogenic and polygenic types. The former are rare, with most migraine considered polygenic, supported by genome-wide association studies (GWAS) identifying numerous genetic variants linked with migraine risk. Surprisingly, some of the most common mutations are associated with transient receptor potential melastatin 8 (TRPM8), a non-selective cation channel that is the primary sensor of cold temperatures in cutaneous primary afferents of the somatosensory system. However, it is unlikely that the temperature sensitivity of TRPM8 is relevant in migraine-related tissues, such as the meninges, suggesting other activation mechanisms underly its role in migraine pathogenesis. Thus, to define the basis of the channel's involvement, we reasoned that cellular processes that increase cold sensitivity in the skin, such as the neurotrophic factor artemin, via its receptor glial cell-line derived neurotrophic factor family receptor alpha-3 (GFRα3), also mediate TRPM8-associated migraine-like pain in the meninges. METHODS To investigate the role of artemin and GFRα3 in preclinical rodent migraine models, we infused nitroglycerin acutely and chronically, and measured changes in periorbital and hind paw mechanical sensitivity in male and female mice lacking GFRα3, after neutralization of free artemin with specific monoclonal antibodies, or by systemic treatment with a TRPM8-specific antagonist. Further, in mice lacking GFRα3 we tested the effects of supradural infusions of a mix of inflammatory mediators, as well as tested if dura stimulation with artemin or a TRPM8-specific agonist induce migraine-related pain in mice. RESULTS We find that mechanical allodynia induced by systemic nitroglycerin, or supradural infusion of inflammatory mediators, involves GFRα3. In addition, neutralization of circulating artemin reduces the nitroglycerin phenotype, demonstrating the importance of this neurotrophic pathway in headaches. Further, we show TRPM8 expression in the meninges, and that direct supradural infusion of either a TRPM8-specific agonist or artemin itself produces mechanical allodynia, with the latter dependent on TRPM8 and ameliorated by concurrent treatment with sumatriptan. CONCLUSIONS These results indicate that neuroinflammatory events in the meninges can produce migraine-like pain in mice via artemin and GFRα3, likely acting upstream of TRPM8, providing a novel pathway that may contribute to headaches or migraine pathogenesis.
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Affiliation(s)
- Chenyu Yang
- Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
- Molecular and Computational Biology Graduate Program, University of Southern California, Los Angeles, CA, USA
| | - Chao Wei
- Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
- Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Sanaa Alam
- Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
| | - Xunyang Chen
- Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
| | - David D McKemy
- Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
- Molecular and Computational Biology Graduate Program, University of Southern California, Los Angeles, CA, USA
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Lee PR, Ha T, Choi HS, Lee SE, Kim C, Hong GS. Piezo1 mediates mechanical signals in TRPV1-positive nociceptors in mice. Acta Physiol (Oxf) 2024; 240:e14236. [PMID: 39324481 DOI: 10.1111/apha.14236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 09/11/2024] [Accepted: 09/13/2024] [Indexed: 09/27/2024]
Abstract
AIM This investigation addresses Piezo1's expression and mechanistic role in dorsal root ganglion (DRG) neurons and delineates its participation in mechanical and inflammatory pain modulation. METHODS We analyzed Piezo1's expression patterns in DRG neurons and utilized Piezo1-specific shRNA to modulate its activity. Electrophysiological assessments of mechanically activated (MA) currents in DRG neurons and behavioral analyses in mouse models of inflammatory pain were conducted to elucidate Piezo1's functional implications. Additionally, we investigated the excitability of TRPV1-expressing DRG neurons, particularly under inflammatory conditions. RESULTS Piezo1 was preferentially expressed in DRG neurons co-expressing the TRPV1 nociceptor marker. Knockdown of Piezo1 attenuated intermediately adapting MA currents and lessened tactile pain hypersensitivity in models of inflammatory pain. Additionally, silencing Piezo1 modified the excitability of TRPV1-expressing neurons under inflammatory stress. CONCLUSION Piezo1 emerges as a key mediator in the transmission of mechanical and inflammatory pain, indicating its potential as a novel target for pain management therapies. Our finding not only advances the understanding of nociceptive signaling but also emphasizes the therapeutic potential of modulating Piezo1 in the treatment of pain.
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Affiliation(s)
- Pa Reum Lee
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
| | - Taewoong Ha
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
- Department of Life Sciences, Korea University, Seoul, Republic of Korea
| | - Hoon-Seong Choi
- Research Animal Resource Center, KIST, Seoul, Republic of Korea
| | - Seung Eun Lee
- Research Animal Resource Center, KIST, Seoul, Republic of Korea
| | - Chungho Kim
- Department of Life Sciences, Korea University, Seoul, Republic of Korea
| | - Gyu-Sang Hong
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
- Department of Life Sciences, Korea University, Seoul, Republic of Korea
- Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
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5
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Briânis RC, Andreotti JP, Moreira FA, Iglesias LP. Interplay between endocannabinoid and endovanilloid mechanisms in fear conditioning. Acta Neuropsychiatr 2024; 36:255-264. [PMID: 37982167 DOI: 10.1017/neu.2023.54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
OBJECTIVE The transient receptor potential cation channel, subfamily V (vanilloid), member 1 (TRPV1) mediates pain perception to thermal and chemical stimuli in peripheral neurons. The cannabinoid receptor type 1 (CB1), on the other hand, promotes analgesia in both the periphery and the brain. TRPV1 and CB1 have also been implicated in learned fear, which involves the association of a previously neutral stimulus with an aversive event. In this review, we elaborate on the interplay between CB1 receptors and TRPV1 channels in learned fear processing. METHODS We conducted a PubMed search for a narrative review on endocannabinoid and endovanilloid mechanisms on fear conditioning. RESULTS TRPV1 and CB1 receptors are activated by a common endogenous agonist, arachidonoyl ethanolamide (anandamide), Moreover, they are expressed in common neuroanatomical structures and recruit converging cellular pathways, acting in concert to modulate fear learning. However, evidence suggests that TRPV1 exerts a facilitatory role, whereas CB1 restrains fear responses. CONCLUSION TRPV1 and CB1 seem to mediate protective and aversive roles of anandamide, respectively. However, more research is needed to achieve a better understanding of how these receptors interact to modulate fear learning.
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Affiliation(s)
- Rayssa C Briânis
- Department of Pharmacology, Institute of Biological Sciences; Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Julia P Andreotti
- Department of Pharmacology, Institute of Biological Sciences; Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Fabrício A Moreira
- Department of Pharmacology, Institute of Biological Sciences; Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Lia P Iglesias
- Department of Pharmacology, Institute of Biological Sciences; Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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6
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Manti S, Gambadauro A, Galletta F, Ruggeri P, Piedimonte G. Update on the Role of β2AR and TRPV1 in Respiratory Diseases. Int J Mol Sci 2024; 25:10234. [PMID: 39408565 PMCID: PMC11477158 DOI: 10.3390/ijms251910234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 09/16/2024] [Accepted: 09/23/2024] [Indexed: 10/20/2024] Open
Abstract
Respiratory diseases (RDs) constitute a common public health problem both in industrialized and developing countries. The comprehension of the pathophysiological mechanisms underlying these conditions and the development of new therapeutic strategies are critical for improving the quality of life of affected patients. β2-adrenergic receptor (β2AR) and transient receptor potential vanilloid 1 (TRPV1) are both involved in physiological responses in the airways. β2AR is implicated in bronchodilation, mucociliary clearance, and anti-inflammatory effects, while TRPV1 is involved in the mediation of pain and cough reflexes. In RDs, such as respiratory infections, asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, the concentration and expression of these receptors can be altered, leading to significant consequences. In this review, we provided an update on the literature about the role of β2AR and TRPV1 in these conditions. We reported how the diminished or defective expression of β2AR during viral infections or prolonged therapy with β2-agonists can increase the severity of these pathologies and impact the prognosis. Conversely, the role of TRPV1 was pivotal in neuroinflammation, and its modulation could lead to innovative treatment strategies in specific patients. We indicate future perspectives and potential personalized treatments in RDs through a comprehensive analysis of the roles of these receptors in the physiological and pathological mechanisms of these pathologies.
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Affiliation(s)
- Sara Manti
- Pediatric Unit, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, Via Consolare Valeria 1, 98124 Messina, Italy; (S.M.); (F.G.)
| | - Antonella Gambadauro
- Pediatric Unit, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, Via Consolare Valeria 1, 98124 Messina, Italy; (S.M.); (F.G.)
| | - Francesca Galletta
- Pediatric Unit, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, Via Consolare Valeria 1, 98124 Messina, Italy; (S.M.); (F.G.)
| | - Paolo Ruggeri
- Pulmonology Unit, Department of Biomedical and Dental Sciences, University of Messina, Via Consolare Valeria 1, 98124 Messina, Italy
| | - Giovanni Piedimonte
- Office for Research and Departments of Pediatrics, Biochemistry, and Molecular Biology, Tulane University, New Orleans, LA 70112, USA;
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7
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Yang C, Wei C, Alam S, Chen X, McKemy DD. The neurotrophic factor artemin and its receptor GFRα3 mediate migraine-like pain via the ion channel TRPM8. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.09.611532. [PMID: 39314341 PMCID: PMC11419092 DOI: 10.1101/2024.09.09.611532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Background Migraine has a strong genetic foundation, including both monogenic and polygenic types. The former are rare, with most migraine considered polygenic, supported by genome-wide association studies (GWAS) identifying numerous genetic variants associated with migraine risk. Surprisingly, some of the most common mutations are associated with TRPM8, a non-selective cation channel that is the primary sensor of cold temperatures in primary afferent neurons of the somatosensory system. However, it is unlikely that the temperature sensitivity of TRPM8 underlies its role in migraine pathogenesis. To define the basis of the channel's involvement, we reasoned that cellular processes that increase cold sensitivity in the skin, such as the neurotrophic factor artemin, via its receptor GFRα3, also mediate TRPM8-associated migraine-like pain in the meninges. Methods To investigate the role of artemin and GFRα3 in preclinical rodent migraine models, we infused nitroglycerin acutely and chronically, and measured changes in periorbital and hind paw mechanical sensitivity in male and female mice lacking GFRα3, after neutralization of free artemin with specific monoclonal antibodies, or by systemic treatment with a TRPM8-specific antagonist. Further, in wildtypes and mice lacking either GFRα3 or TRPM8, we tested the effects of supradural infusions of a mix of inflammatory mediators, artemin, and a TRPM8-specific agonist on migraine-related pain in mice. Results We find that mechanical allodynia induced by systemic nitroglycerin, or supradural infusion of inflammatory mediators, involves GFRα3. In addition, neutralization of circulating artemin reduces the nitroglycerin phenotype, demonstrating the importance of this neurotrophic pathway. Further, we show TRPM8 expression in the meninges and that direct supradural infusion of either a TRPM8-specific agonist or artemin itself produces mechanical allodynia, the latter dependent on TRPM8 and ameliorated by concurrent treatment with sumatriptan. Conclusions These results indicate that neuroinflammatory events in the meninges can produce migraine-like pain in mice via artemin and GFRα3, likely acting upstream of TRPM8, providing a novel pathway that may contribute to migraine pathogenesis.
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Affiliation(s)
- Chenyu Yang
- Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089
- Molecular and Computational Biology Graduate Program, University of Southern California, Los Angeles, CA 90089
| | - Chao Wei
- Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089
- Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
| | - Sanaa Alam
- Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089
| | - Xunyang Chen
- Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089
| | - David D. McKemy
- Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089
- Molecular and Computational Biology Graduate Program, University of Southern California, Los Angeles, CA 90089
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8
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Gualdani R, Barbeau S, Yuan JH, Jacobs DS, Gailly P, Dib-Hajj SD, Waxman SG. TRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization. Proc Natl Acad Sci U S A 2024; 121:e2406186121. [PMID: 39226353 PMCID: PMC11406256 DOI: 10.1073/pnas.2406186121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 07/30/2024] [Indexed: 09/05/2024] Open
Abstract
The factors that contribute to pain after nerve injury remain incompletely understood. Laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) are common surgical techniques to correct refractive errors. After LASIK or PRK, a subset of patients suffers intense and persistent pain, of unknown origin, described by patients as feeling like shards of glass in their eye. Here, we evaluated a TRPV1 variant, p.V527M, found in a 49-y-old woman who developed corneal pain after LASIK and subsequent PRK enhancement, reporting an Ocular Surface Disease Index score of 100. Using patch-clamp and Ca2+ imaging, we found that the V527M mutation enhances the response to acidic pH. Increasing proton concentration induced a stronger leftward shift in the activation curve of V527M compared to WT, resulting in channel activity of the mutant in acidic pH at more physiological membrane potentials. Finally, comparing the responses to consecutive applications of different agonists, we found in V527M channels a reduced capsaicin-induced desensitization and increased sensitization by the arachidonic acid metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). We hypothesize that the increased response in V527M channels to protons and enhanced sensitization by 12-HETE, two inflammatory mediators released in the cornea after tissue damage, may contribute to the pathogenesis of corneal neuralgia after refractive surgery.
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Affiliation(s)
- Roberta Gualdani
- Laboratory of Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, BrusselsB-1200, Belgium
| | - Solène Barbeau
- Laboratory of Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, BrusselsB-1200, Belgium
| | - Jun-Hui Yuan
- Department of Neurology, Yale School of Medicine, New Haven, CT06520
- Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, CT06520
- Neurorehabilitation Research Center, Veterans Affairs Medical Center, West Haven, CT06516
| | - Deborah S. Jacobs
- Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA02114
| | - Philippe Gailly
- Laboratory of Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, BrusselsB-1200, Belgium
| | - Sulayman D. Dib-Hajj
- Department of Neurology, Yale School of Medicine, New Haven, CT06520
- Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, CT06520
- Neurorehabilitation Research Center, Veterans Affairs Medical Center, West Haven, CT06516
| | - Stephen G. Waxman
- Department of Neurology, Yale School of Medicine, New Haven, CT06520
- Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, CT06520
- Neurorehabilitation Research Center, Veterans Affairs Medical Center, West Haven, CT06516
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Gao N, Li M, Wang W, Liu Z, Guo Y. The dual role of TRPV1 in peripheral neuropathic pain: pain switches caused by its sensitization or desensitization. Front Mol Neurosci 2024; 17:1400118. [PMID: 39315294 PMCID: PMC11417043 DOI: 10.3389/fnmol.2024.1400118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 08/12/2024] [Indexed: 09/25/2024] Open
Abstract
The transient receptor potential vanilloid 1 (TRPV1) channel plays a dual role in peripheral neuropathic pain (NeuP) by acting as a "pain switch" through its sensitization and desensitization. Hyperalgesia, commonly resulting from tissue injury or inflammation, involves the sensitization of TRPV1 channels, which modulates sensory transmission from primary afferent nociceptors to spinal dorsal horn neurons. In chemotherapy-induced peripheral neuropathy (CIPN), TRPV1 is implicated in neuropathic pain mechanisms due to its interaction with ion channels, neurotransmitter signaling, and oxidative stress. Sensitization of TRPV1 in dorsal root ganglion neurons contributes to CIPN development, and inhibition of TRPV1 channels can reduce chemotherapy-induced mechanical hypersensitivity. In diabetic peripheral neuropathy (DPN), TRPV1 is involved in pain modulation through pathways including reactive oxygen species and cytokine production. TRPV1's interaction with TRPA1 channels further influences chronic pain onset and progression. Therapeutically, capsaicin, a TRPV1 agonist, can induce analgesia through receptor desensitization, while TRPV1 antagonists and siRNA targeting TRPV1 show promise in preclinical studies. Cannabinoid modulation of TRPV1 provides another potential pathway for alleviating neuropathic pain. This review summarizes recent preclinical research on TRPV1 in association with peripheral NeuP.
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Affiliation(s)
- Ning Gao
- Department of Acupuncture and Moxibustion, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Meng Li
- Department of Gastroenterology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Weiming Wang
- Department of Acupuncture and Moxibustion, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhen Liu
- Department of Gastroenterology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yufeng Guo
- Department of Acupuncture and Moxibustion, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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10
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Barrett KT, Roy A, Ebdalla A, Pittman QJ, Wilson RJA, Scantlebury MH. The Impact of Inflammation on Thermal Hyperpnea: Relevance for Heat Stress and Febrile Seizures. Am J Respir Cell Mol Biol 2024; 71:195-206. [PMID: 38597725 PMCID: PMC11299082 DOI: 10.1165/rcmb.2023-0451oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 04/09/2024] [Indexed: 04/11/2024] Open
Abstract
Extreme heat caused by climate change is increasing the transmission of infectious diseases, resulting in a sharp rise in heat-related illness and mortality. Understanding the mechanistic link between heat, inflammation, and disease is thus important for public health. Thermal hyperpnea, and consequent respiratory alkalosis, is crucial in febrile seizures and convulsions induced by heat stress in humans. Here, we address what causes thermal hyperpnea in neonates and how it is affected by inflammation. Transient receptor potential cation channel subfamily V member 1 (TRPV1), a heat-activated channel, is sensitized by inflammation and modulates breathing and thus may play a key role. To investigate whether inflammatory sensitization of TRPV1 modifies neonatal ventilatory responses to heat stress, leading to respiratory alkalosis and an increased susceptibility to hyperthermic seizures, we treated neonatal rats with bacterial LPS, and breathing, arterial pH, in vitro vagus nerve activity, and seizure susceptibility were assessed during heat stress in the presence or absence of a TRPV1 antagonist (AMG-9810) or shRNA-mediated TRPV1 suppression. LPS-induced inflammatory preconditioning lowered the threshold temperature and latency of hyperthermic seizures. This was accompanied by increased tidal volume, minute ventilation, expired CO2, and arterial pH (alkalosis). LPS exposure also elevated vagal spiking and intracellular calcium concentrations in response to hyperthermia. TRPV1 inhibition with AMG-9810 or shRNA reduced the LPS-induced susceptibility to hyperthermic seizures and altered the breathing pattern to fast shallow breaths (tachypnea), making each breath less efficient and restoring arterial pH. These results indicate that inflammation exacerbates thermal hyperpnea-induced respiratory alkalosis associated with increased susceptibility to hyperthermic seizures, primarily mediated by TRPV1 localized to vagus neurons.
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Affiliation(s)
- Karlene T. Barrett
- Alberta Children’s Hospital Research Institute
- Hotchkiss Brain Institute
- Department of Pediatrics
| | - Arijit Roy
- Hotchkiss Brain Institute
- Department of Physiology and Pharmacology, and
| | - Aya Ebdalla
- Alberta Children’s Hospital Research Institute
| | - Quentin J. Pittman
- Alberta Children’s Hospital Research Institute
- Hotchkiss Brain Institute
- Department of Physiology and Pharmacology, and
| | - Richard J. A. Wilson
- Alberta Children’s Hospital Research Institute
- Hotchkiss Brain Institute
- Department of Physiology and Pharmacology, and
| | - Morris H. Scantlebury
- Alberta Children’s Hospital Research Institute
- Hotchkiss Brain Institute
- Department of Pediatrics
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
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11
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Almousa AS, Subash-Babu P, Alanazi IO, Alshatwi AA, Alkhalaf H, Bahattab E, Alsiyah A, Alzahrani M. Hemp Seed Oil Inhibits the Adipogenicity of the Differentiation-Induced Human Mesenchymal Stem Cells through Suppressing the Cannabinoid Type 1 (CB1). Molecules 2024; 29:1568. [PMID: 38611847 PMCID: PMC11013118 DOI: 10.3390/molecules29071568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 03/28/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
Central and peripheral mechanisms of the endocannabinoid system (ECS) favor energy intake and storage. The ECS, especially cannabidiol (CBD) receptors, controls adipocyte differentiation (hyperplasia) and lipid accumulation (hypertrophy) in adipose tissue. In white adipose tissue, cannabidiol receptor 1 (CB1) stimulation increases lipogenesis and inhibits lipolysis; in brown adipose tissue, it decreases mitochondrial thermogenesis and biogenesis. This study compared the availability of phytocannabinoids [CBD and Δ9-tetrahydrocannabinol (THC)] and polyunsaturated fatty acids [omega 3 (ω3) and omega 6 (ω6)] in different hemp seed oils (HSO). The study also examined the effect of HSO on adipocyte lipid accumulation by suppressing cannabinoid receptors in adipogenesis-stimulated human mesenchymal stem cells (hMSCs). Most importantly, Oil-Red-O' and Nile red tests showed that HSO induced adipogenic hMSC differentiation without differentiation agents. Additionally, HSO-treated cells showed increased peroxisome proliferator-activated receptor gamma (PPARγ) mRNA expression compared to controls (hMSC). HSO reduced PPARγ mRNA expression after differentiation media (DM) treatment. After treatment with HSO, DM-hMSCs had significantly lower CB1 mRNA and protein expressions than normal hMSCs. HSO treatment also decreased transient receptor potential vanilloid 1 (TRPV1), fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MGL) mRNAs in hMSC and DM-hMSCs. HSO treatment significantly decreased CB1, CB2, TRPV1, and G-protein-coupled receptor 55 (GPCR55) protein levels in DM-hMSC compared to hMSC in western blot analysis. In this study, HSO initiated adipogenic differentiation in hMSC without DM, but it suppressed CB1 gene and protein expression, potentially decreasing adipocyte lipid accumulation and lipogenic enzymes.
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Affiliation(s)
- Albatul S. Almousa
- Department of Food Science and Nutrition, College of Food Science and Agriculture, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia;
- Department of Human Nutrition, College of Home Economics, King Khalid University, P.O. Box 3236, Abha 10001, Saudi Arabia
| | - Pandurangan Subash-Babu
- Department of Food Science and Nutrition, College of Food Science and Agriculture, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia;
| | - Ibrahim O. Alanazi
- The Healthy Aging Research Institute, King Abdulaziz City for Science and Technology, P.O. Box 6086, Riyadh 11442, Saudi Arabia; (I.O.A.); (H.A.); (E.B.)
- Genome Research Unit, Department of Biochemistry, College of Science, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia
| | - Ali A. Alshatwi
- Department of Food Science and Nutrition, College of Food Science and Agriculture, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia;
| | - Huda Alkhalaf
- The Healthy Aging Research Institute, King Abdulaziz City for Science and Technology, P.O. Box 6086, Riyadh 11442, Saudi Arabia; (I.O.A.); (H.A.); (E.B.)
| | - Eman Bahattab
- The Healthy Aging Research Institute, King Abdulaziz City for Science and Technology, P.O. Box 6086, Riyadh 11442, Saudi Arabia; (I.O.A.); (H.A.); (E.B.)
| | - Atheer Alsiyah
- The Applied Genomics Research Institute, King Abdulaziz City for Science and Technology, P.O. Box 6086, Riyadh 11442, Saudi Arabia;
| | - Mohammad Alzahrani
- Institute of Advanced Agricultural and Food Technologies, King Abdulaziz City for Science and Technology, P.O. Box 6086, Riyadh 11442, Saudi Arabia;
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Li ZY, Mao YQ, Hua Q, Sun YH, Wang HY, Ye XG, Hu JX, Wang YJ, Jiang M. Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome. World J Gastroenterol 2024; 30:1431-1449. [PMID: 38596485 PMCID: PMC11000090 DOI: 10.3748/wjg.v30.i10.1431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/29/2023] [Accepted: 02/06/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Serotonin receptor 2B (5-HT2B receptor) plays a critical role in many chronic pain conditions. The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea (IBS-D) was investigated in the present study. AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D. METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls. The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores. The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint. Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1 (TRPV1) expression were examined following 5-HT2B receptor antagonist administration. Changes in visceral sensitivity after administration of the TRPV1 antagonist were recorded. RESULTS Here, we observed greater expression of the 5-HT2B receptor in the colonic mucosa of patients with IBS-D than in that of controls, which was correlated with abdominal pain scores. Intracolonic instillation of acetic acid and wrap restraint induced obvious chronic visceral hypersensitivity and increased fecal weight and fecal water content. Exogenous 5-HT2B receptor agonist administration increased visceral hypersensitivity, which was alleviated by successive administration of a TRPV1 antagonist. IBS-D rats receiving the 5-HT2B receptor antagonist exhibited inhibited visceral hyperalgesia.Moreover, the percentage of 5-HT2B receptor-immunoreactive (IR) cells surrounded by TRPV1-positive cells (5-HT2B receptor I+) and total 5-HT2B receptor IR cells (5-HT2B receptor IT) in IBS-D rats was significantly reduced by the administration of a 5-HT2B receptor antagonist. CONCLUSION Our finding that increased expression of the 5-HT2B receptor contributes to visceral hyperalgesia by inducing TRPV1 expression in IBS-D patients provides important insights into the potential mechanisms underlying IBS-D-associated visceral hyperalgesia.
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Affiliation(s)
- Zheng-Yang Li
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Yu-Qing Mao
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Qian Hua
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Yong-Hong Sun
- Department of Gastroenterology, Dalian Friendship Hospital, Dalian 116001, Liaoning Province, China
| | - Hai-Yan Wang
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Xuan-Guang Ye
- Department of Pathology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Jing-Xian Hu
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Ya-Jie Wang
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Miao Jiang
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
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Del Gaudio MP, Kraus SI, Melzer TM, Bustos PS, Ortega MG. Oral treatment with Berberine reduces peripheral nociception: Possible interaction with different nociceptive pathways activated by different allogeneic substances. JOURNAL OF ETHNOPHARMACOLOGY 2024; 321:117504. [PMID: 38061440 DOI: 10.1016/j.jep.2023.117504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 11/20/2023] [Accepted: 11/22/2023] [Indexed: 12/30/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Berberine was identified in extracts of Berberis ruscifolia Lam., a plant used in traditional medicine as an analgesic. Its presence may be involved in the reported pharmacological activity of this species. However, there is still a lack of scientific research concerning its analgesic activity in the peripheral nervous system. AIM OF THE STUDY To investigate Berb-induced antinociception in the formalin test and to evaluate several pathways related to its pharmacological antinociceptive effects in chemical models of nociception in mice. MATERIALS AND METHODS The antinociceptive activity of Berb was assessed by inducing the paw licking in mice with different allodynic agents. In the formalin test, the antiedematous and antithermal effect of Berb was evaluated simultaneously in the same experiment. Other nociceptive behavior produced by endogenous [prostaglandin E2 (PGE2), histamine (His), glutamate (Glu) or bradykinin (BK)] or exogenous [capsaicin (Caps) and cinnamaldehyde (Cin)] chemical stimuli, and activators as protein kinase A (PKA) and C (PKC), were also evaluated.The in vivo doses for p.o. were 3 and 30 mg/kg. RESULTS Berb, at 30 mg/kg p.o., showed a significant inhibition of the nociceptive action in formalin in both phases being stronger at the inflammatory phase (59 ± 9%) and more active than Asp (positive control) considering the doses evaluated. Moreover, Berb inhibited the edema (34 ± 10%), but not the temperature in the formalin test. Regarding the different nociceptive signaling pathways evaluated, the most relevant data were that the administration of p.o. of Berb, at 30 mg/kg, caused significant inhibition of nociception induced by endogenous [His (72 ± 11%), PGE2 (78 ± 4%), and BK (51 ± 7%)], exogenous [Cap (68 ± 4%) and Cinn (57 ± 5%)] compounds, and activators of the PKA [(FSK (86 ± 3%)] and PKC [(PMA(86 ± 6%)] signaling pathway. Berb did not inhibit the nociceptive effect produced by Glu. CONCLUSION The present study demonstrated, for the first time, the potential of Berb in several nociceptive tests, with the compound present in B. ruscifolia contributing to the analgesic effect reported for this species.
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Affiliation(s)
- Micaela Paula Del Gaudio
- Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Córdoba, 5000, Argentina; Instituto Multidisciplinario de Biología Vegetal (IMBIV), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Universidad Nacional de Córdoba, Av. Vélez Sarsfield 1611, Córdoba, 5000, Argentina
| | - Scheila Iria Kraus
- Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center for Biological Sciences, Federal University of Santa Catarina, University Campus, Trindade, Florianópolis, SC, 88040-900, Brazil
| | - Thayza Martins Melzer
- Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center for Biological Sciences, Federal University of Santa Catarina, University Campus, Trindade, Florianópolis, SC, 88040-900, Brazil
| | - Pamela Soledad Bustos
- Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Córdoba, 5000, Argentina; Instituto Multidisciplinario de Biología Vegetal (IMBIV), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Universidad Nacional de Córdoba, Av. Vélez Sarsfield 1611, Córdoba, 5000, Argentina
| | - María Gabriela Ortega
- Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Córdoba, 5000, Argentina; Instituto Multidisciplinario de Biología Vegetal (IMBIV), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Universidad Nacional de Córdoba, Av. Vélez Sarsfield 1611, Córdoba, 5000, Argentina.
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Aldossary SA, Alsalem M, Grubb BD. Role of bradykinin and prostaglandin EP4 receptors in regulating TRPV1 channel sensitization in rat dorsal root ganglion neurons. Basic Clin Pharmacol Toxicol 2024; 134:345-360. [PMID: 38009541 DOI: 10.1111/bcpt.13967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 10/23/2023] [Accepted: 11/22/2023] [Indexed: 11/29/2023]
Abstract
Transient receptor potential vanilloid type-1 (TRPV1) channels play key roles in chronic pain conditions and are modulated by different inflammatory mediators to elicit heat sensitisation. Bradykinin is a 9-amino acid peptide chain that promotes inflammation. The aim of present study is to investigate how bradykinin and prostaglandin receptors (EP3 and EP4 ) modulate the sensitisation of TRPV1-mediated responses. Calcium imaging studies of rat dorsal root ganglion (DRG) neurons were employed to investigate the desensitizing responses of TRPV1 ion channels by capsaicin, and the re-sensitization of TRPV1 by bradykinin, then to explore the role EP3 and EP4 receptors in mediating these bradykinin-dependent effects. Immunocytochemistry was used to study the co-expression and distribution of EP4, TRPV1, COX-1 and B2 in rat DRG neurons. Desensitization was seen upon repeated capsaicin application, we show that bradykinin-mediated sensitization of capsaicin-evoked calcium responses in rat DRG neurons occurs is dependent on COX-1 activity and utilizes a pathway that involves EP4 but not EP3 receptors. Immunocytochemical techniques revealed that EP4, TRPV1, COX-1 and B2 proteins are expressed mainly in small diameter (<1000 μm2 ) cell bodies of rat DRG neurons which are typically nociceptors. The present study provides suggestive evidence for a potential signalling pathway through which bradykinin may regulate TRPV1 ion channel function via EP4 receptors. In addition to confirming existing knowledge, the anatomical distribution and colocalization of these proteins in DRG neurons as revealed by this study offer valuable insight.
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Affiliation(s)
- Sara A Aldossary
- Faculty of Clinical Pharmacy, King Faisal University, Hofuf, Saudi Arabia
| | | | - Blair D Grubb
- Executive Office, University of Dundee, Nethergate, Dundee, DD1 4HN, UK
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15
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Liao Z, Umar M, Huang X, Qin L, Xiao G, Chen Y, Tong L, Chen D. Transient receptor potential vanilloid 1: A potential therapeutic target for the treatment of osteoarthritis and rheumatoid arthritis. Cell Prolif 2024; 57:e13569. [PMID: 37994506 PMCID: PMC10905355 DOI: 10.1111/cpr.13569] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/11/2023] [Accepted: 10/15/2023] [Indexed: 11/24/2023] Open
Abstract
This study aims to determine the molecular mechanisms and analgesic effects of transient receptor potential vanilloid 1 (TRPV1) in the treatments of osteoarthritis (OA) and rheumatoid arthritis (RA). We summarize and analyse current studies regarding the biological functions and mechanisms of TRPV1 in arthritis. We search and analyse the related literature in Google Scholar, Web of Science and PubMed databases from inception to September 2023 through the multi-combination of keywords like 'TRPV1', 'ion channel', 'osteoarthritis', 'rheumatoid arthritis' and 'pain'. TRPV1 plays a crucial role in regulating downstream gene expression and maintaining cellular function and homeostasis, especially in chondrocytes, synovial fibroblasts, macrophages and osteoclasts. In addition, TRPV1 is located in sensory nerve endings and plays an important role in nerve sensitization, defunctionalization or central sensitization. TRPV1 is a non-selective cation channel protein. Extensive evidence in recent years has established the significant involvement of TRPV1 in the development of arthritis pain and inflammation, positioning it as a promising therapeutic target for arthritis. TRPV1 likely represents a feasible therapeutic target for the treatment of OA and RA.
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Affiliation(s)
- Zhidong Liao
- Department of Bone and Joint Surgerythe First Affiliated Hospital of Guangxi Medical UniversityNanningChina
- Research Center for Computer‐aided Drug Discovery, Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenChina
- Faculty of Pharmaceutical SciencesShenzhen Institute of Advanced TechnologyShenzhenChina
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co‐constructed by the Province and MinistryGuangxi Medical UniversityNanningGuangxiChina
| | - Muhammad Umar
- Research Center for Computer‐aided Drug Discovery, Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenChina
- Faculty of Pharmaceutical SciencesShenzhen Institute of Advanced TechnologyShenzhenChina
| | - Xingyun Huang
- Research Center for Computer‐aided Drug Discovery, Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenChina
- Faculty of Pharmaceutical SciencesShenzhen Institute of Advanced TechnologyShenzhenChina
| | - Ling Qin
- Musculoskeletal Research Laboratory of Department of Orthopaedics & Traumatology and Innovative Orthopaedic Biomaterial & Drug Translational Research LaboratoryLi Ka Shing Institute of Health Sciences, The Chinese University of Hong KongHong KongChina
| | - Guozhi Xiao
- School of MedicineSouthern University of Science and TechnologyShenzhenChina
| | - Yan Chen
- Department of Bone and Joint Surgerythe First Affiliated Hospital of Guangxi Medical UniversityNanningChina
| | - Liping Tong
- Research Center for Computer‐aided Drug Discovery, Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenChina
| | - Di Chen
- Research Center for Computer‐aided Drug Discovery, Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenChina
- Faculty of Pharmaceutical SciencesShenzhen Institute of Advanced TechnologyShenzhenChina
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16
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Mardelle U, Bretaud N, Daher C, Feuillet V. From pain to tumor immunity: influence of peripheral sensory neurons in cancer. Front Immunol 2024; 15:1335387. [PMID: 38433844 PMCID: PMC10905387 DOI: 10.3389/fimmu.2024.1335387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/29/2024] [Indexed: 03/05/2024] Open
Abstract
The nervous and immune systems are the primary sensory interfaces of the body, allowing it to recognize, process, and respond to various stimuli from both the external and internal environment. These systems work in concert through various mechanisms of neuro-immune crosstalk to detect threats, provide defense against pathogens, and maintain or restore homeostasis, but can also contribute to the development of diseases. Among peripheral sensory neurons (PSNs), nociceptive PSNs are of particular interest. They possess a remarkable capability to detect noxious stimuli in the periphery and transmit this information to the brain, resulting in the perception of pain and the activation of adaptive responses. Pain is an early symptom of cancer, often leading to its diagnosis, but it is also a major source of distress for patients as the disease progresses. In this review, we aim to provide an overview of the mechanisms within tumors that are likely to induce cancer pain, exploring a range of factors from etiological elements to cellular and molecular mediators. In addition to transmitting sensory information to the central nervous system, PSNs are also capable, when activated, to produce and release neuropeptides (e.g., CGRP and SP) from their peripheral terminals. These neuropeptides have been shown to modulate immunity in cases of inflammation, infection, and cancer. PSNs, often found within solid tumors, are likely to play a significant role in the tumor microenvironment, potentially influencing both tumor growth and anti-tumor immune responses. In this review, we discuss the current state of knowledge about the degree of sensory innervation in tumors. We also seek to understand whether and how PSNs may influence the tumor growth and associated anti-tumor immunity in different mouse models of cancer. Finally, we discuss the extent to which the tumor is able to influence the development and functions of the PSNs that innervate it.
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Affiliation(s)
- Ugo Mardelle
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Ninon Bretaud
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Clara Daher
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Vincent Feuillet
- Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
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17
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Wen X, Feng X, Xin F, An R, Huang H, Mao L, Liu P, Zhang J, Huang H, Liu X, Wang W. B. vulgatus ameliorates high-fat diet-induced obesity through modulating intestinal serotonin synthesis and lipid absorption in mice. Gut Microbes 2024; 16:2423040. [PMID: 39569932 PMCID: PMC11583587 DOI: 10.1080/19490976.2024.2423040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/12/2024] [Accepted: 10/24/2024] [Indexed: 11/22/2024] Open
Abstract
The consumption of high-fat diets (HFD) and an imbalance in gut microbiome are linked to obesity. However, the intricate connection between them and the underlying mechanisms involved in lipid digestion and absorption remain largely unclear. This study shows that after 12 weeks of HFD feeding, C57BL/6J mice exhibit two distinct metabolic phenotypes with significant differences in gut microbiota composition. The LOW and LOW FMT group mice with increased Bacteroides are protected from obesity, insulin resistance, and lipid accumulation. Supplementation with B. vulgatus or cholic acid (CA) alleviates HFD-induced obesity and metabolic dysfunction. This is due to the accumulation of lipid droplets and the retention of chyle particles in jejunal epithelial cells, which reduces chyle intake in the jejunal mesentery after HFD. Decreased 5-HT synthesis in the jejunal enterochromaffin cells of these mice, along with reduced chyle intake in the jejunal mesentery after HFD in Tph1△IEC, suggests that intestinal 5-HT is required for host lipid absorption. TRPV1, a calcium-permeable ion channel, mediates the basolateral 5-HT-induced increase of Isc and ion channel open probability. This study uncovers a novel signaling axis of microbiota-metabolite-5-HT and intracellular calcium-dependent lipid absorption, which may serve as the potential therapeutic targets for treating HFD-induced obesity.
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Affiliation(s)
- Xinxin Wen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiaoyan Feng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Fang Xin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Rui An
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Huanwei Huang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Liyuan Mao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Ping Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Jin Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Haixia Huang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xicheng Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- Laboratory for Clinical Medicine, Beijing Key Laboratory for Tumor Invasion and Metastasis, Capital Medical University, Beijing, China
| | - Wei Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
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18
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Daniluk J, Voets T. pH-dependent modulation of TRPV1 by modality-selective antagonists. Br J Pharmacol 2023; 180:2750-2761. [PMID: 37350138 DOI: 10.1111/bph.16173] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 05/10/2023] [Accepted: 06/13/2023] [Indexed: 06/24/2023] Open
Abstract
BACKGROUND AND PURPOSE Antagonists of TRPV1 that inhibit all activation modes cause hyperthermia, hampering their medical use as novel analgesics. TRPV1 antagonists that do not (fully) inhibit responses to low pH do not cause hyperthermia, but it remains incompletely understood how such antagonists affect channel gating. We tested the hypothesis that pH-sparing antagonists act in a modality-selective manner on TRPV1, differentially affecting channel activation by protons and capsaicin. EXPERIMENTAL APPROACH Using whole-cell patch-clamp and calcium imaging to measure channel activity in cells expressing wild type human TRPV1 or the pH-insensitive mutant F660A. Responses to protons and capsaicin were measured at different pH values in the presence of antagonists that reportedly partially spare (A-1165442) or potentiate (AMG7905) acid-evoked channel activation. KEY RESULTS At pH 5.5, A-1165442 was equipotent at blocking acid- and capsaicin-evoked responses of wild type TRPV1. Its potency to inhibit acid-evoked responses was attenuated at pH ≤ 5.0. AMG7905, at a concentration (1 μM) that fully inhibits capsaicin-evoked responses, potentiated proton-evoked (pH 5.5) responses of wild type TRPV1. In the F660A mutant, the inhibitory efficacy of A-1165442 and AMG7905 towards capsaicin-evoked responses was reduced at lower pH values and AMG7905 acted as a partial agonist. CONCLUSION AND IMPLICATIONS Our findings show that A-1165442 and AMG7905 interact in a pH-dependent manner with TRPV1, but this pH dependence is not strictly modality-selective. Reduced TRPV1 antagonism at acidic pH may limit analgesic efficacy in injured tissue and needs to be considered in models explaining the effects of antagonists on core body temperature.
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Affiliation(s)
- Jan Daniluk
- Laboratory of Ion Channel Research (LICR), VIB-KU Leuven Centre for Brain & Disease Research, Leuven, Belgium
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Thomas Voets
- Laboratory of Ion Channel Research (LICR), VIB-KU Leuven Centre for Brain & Disease Research, Leuven, Belgium
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
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Szallasi A. Resiniferatoxin: Nature's Precision Medicine to Silence TRPV1-Positive Afferents. Int J Mol Sci 2023; 24:15042. [PMID: 37894723 PMCID: PMC10606200 DOI: 10.3390/ijms242015042] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/27/2023] [Accepted: 10/07/2023] [Indexed: 10/29/2023] Open
Abstract
Resiniferatoxin (RTX) is an ultrapotent capsaicin analog with a unique spectrum of pharmacological actions. The therapeutic window of RTX is broad, allowing for the full desensitization of pain perception and neurogenic inflammation without causing unacceptable side effects. Intravesical RTX was shown to restore continence in a subset of patients with idiopathic and neurogenic detrusor overactivity. RTX can also ablate sensory neurons as a "molecular scalpel" to achieve permanent analgesia. This targeted (intrathecal or epidural) RTX therapy holds great promise in cancer pain management. Intra-articular RTX is undergoing clinical trials to treat moderate-to-severe knee pain in patients with osteoarthritis. Similar targeted approaches may be useful in the management of post-operative pain or pain associated with severe burn injuries. The current state of this field is reviewed, from preclinical studies through veterinary medicine to clinical trials.
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Affiliation(s)
- Arpad Szallasi
- Department of Pathology and Experimental Cancer Research, Semmelweis University, 1083 Budapest, Hungary
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20
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Leigh SJ, Uhlig F, Wilmes L, Sanchez-Diaz P, Gheorghe CE, Goodson MS, Kelley-Loughnane N, Hyland NP, Cryan JF, Clarke G. The impact of acute and chronic stress on gastrointestinal physiology and function: a microbiota-gut-brain axis perspective. J Physiol 2023; 601:4491-4538. [PMID: 37756251 DOI: 10.1113/jp281951] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
The physiological consequences of stress often manifest in the gastrointestinal tract. Traumatic or chronic stress is associated with widespread maladaptive changes throughout the gut, although comparatively little is known about the effects of acute stress. Furthermore, these stress-induced changes in the gut may increase susceptibility to gastrointestinal disorders and infection, and impact critical features of the neural and behavioural consequences of the stress response by impairing gut-brain axis communication. Understanding the mechanisms behind changes in enteric nervous system circuitry, visceral sensitivity, gut barrier function, permeability, and the gut microbiota following stress is an important research objective with pathophysiological implications in both neurogastroenterology and psychiatry. Moreover, the gut microbiota has emerged as a key aspect of physiology sensitive to the effects of stress. In this review, we focus on different aspects of the gastrointestinal tract including gut barrier function as well as the immune, humoral and neuronal elements involved in gut-brain communication. Furthermore, we discuss the evidence for a role of stress in gastrointestinal disorders. Existing gaps in the current literature are highlighted, and possible avenues for future research with an integrated physiological perspective have been suggested. A more complete understanding of the spatial and temporal dynamics of the integrated host and microbial response to different kinds of stressors in the gastrointestinal tract will enable full exploitation of the diagnostic and therapeutic potential in the fast-evolving field of host-microbiome interactions.
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Affiliation(s)
- Sarah-Jane Leigh
- APC Microbiome Ireland, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Friederike Uhlig
- APC Microbiome Ireland, Cork, Ireland
- Department of Physiology, University College Cork, Cork, Ireland
| | - Lars Wilmes
- APC Microbiome Ireland, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Paula Sanchez-Diaz
- APC Microbiome Ireland, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Cassandra E Gheorghe
- APC Microbiome Ireland, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Michael S Goodson
- 711th Human Performance Wing, Air Force Research Laboratory, Wright-Patterson Air Force Base, Dayton, Ohio, USA
| | - Nancy Kelley-Loughnane
- Materials and Manufacturing Directorate, Air Force Research Laboratory, Wright-Patterson Air Force Base, Dayton, Ohio, USA
| | - Niall P Hyland
- APC Microbiome Ireland, Cork, Ireland
- Department of Physiology, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
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21
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Jesus RLC, Araujo FA, Alves QL, Dourado KC, Silva DF. Targeting temperature-sensitive transient receptor potential channels in hypertension: far beyond the perception of hot and cold. J Hypertens 2023; 41:1351-1370. [PMID: 37334542 DOI: 10.1097/hjh.0000000000003487] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Transient receptor potential (TRP) channels are nonselective cation channels and participate in various physiological roles. Thus, changes in TRP channel function or expression have been linked to several disorders. Among the many TRP channel subtypes, the TRP ankyrin type 1 (TRPA1), TRP melastatin type 8 (TRPM8), and TRP vanilloid type 1 (TRPV1) channels are temperature-sensitive and recognized as thermo-TRPs, which are expressed in the primary afferent nerve. Thermal stimuli are converted into neuronal activity. Several studies have described the expression of TRPA1, TRPM8, and TRPV1 in the cardiovascular system, where these channels can modulate physiological and pathological conditions, including hypertension. This review provides a complete understanding of the functional role of the opposing thermo-receptors TRPA1/TRPM8/TRPV1 in hypertension and a more comprehensive appreciation of TRPA1/TRPM8/TRPV1-dependent mechanisms involved in hypertension. These channels varied activation and inactivation have revealed a signaling pathway that may lead to innovative future treatment options for hypertension and correlated vascular diseases.
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Affiliation(s)
- Rafael Leonne C Jesus
- Laboratory of Cardiovascular Physiology and Pharmacology, Federal University of Bahia, Salvador
| | - Fênix A Araujo
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation - FIOCRUZ, Bahia, Brazil
| | - Quiara L Alves
- Laboratory of Cardiovascular Physiology and Pharmacology, Federal University of Bahia, Salvador
| | - Keina C Dourado
- Laboratory of Cardiovascular Physiology and Pharmacology, Federal University of Bahia, Salvador
| | - Darizy F Silva
- Laboratory of Cardiovascular Physiology and Pharmacology, Federal University of Bahia, Salvador
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation - FIOCRUZ, Bahia, Brazil
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22
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Erin N, Szallasi A. Carcinogenesis and Metastasis: Focus on TRPV1-Positive Neurons and Immune Cells. Biomolecules 2023; 13:983. [PMID: 37371563 DOI: 10.3390/biom13060983] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/23/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Both sensory neurons and immune cells, albeit at markedly different levels, express the vanilloid (capsaicin) receptor, Transient Receptor Potential, Vanilloid-1 (TRPV1). Activation of TRPV1 channels in sensory afferent nerve fibers induces local effector functions by releasing neuropeptides (most notably, substance P) which, in turn, trigger neurogenic inflammation. There is good evidence that chronic activation or inactivation of this inflammatory pathway can modify tumor growth and metastasis. TRPV1 expression was also demonstrated in a variety of mammalian immune cells, including lymphocytes, dendritic cells, macrophages and neutrophils. Therefore, the effects of TRPV1 agonists and antagonists may vary depending on the prominent cell type(s) activated and/or inhibited. Therefore, a comprehensive understanding of TRPV1 activity on immune cells and nerve endings in distinct locations is necessary to predict the outcome of therapies targeting TRPV1 channels. Here, we review the neuro-immune modulation of cancer growth and metastasis, with focus on the consequences of TRPV1 activation in nerve fibers and immune cells. Lastly, the potential use of TRPV1 modulators in cancer therapy is discussed.
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Affiliation(s)
- Nuray Erin
- Department of Medical Pharmacology, School of Medicine, Akdeniz University, Antalya 07070, Turkey
- Immuno-Pharmacology and Immuno-Oncology Unit, School of Medicine, Akdeniz University, Antalya 07070, Turkey
| | - Arpad Szallasi
- Department of Pathology and Experimental Cancer Research, Semmelweis University, H-1085 Budapest, Hungary
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23
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Navia-Pelaez JM, Lemes JBP, Gonzalez L, Delay L, dos Santos Aggum Capettini L, Lu JW, Dos Santos GG, Gregus AM, Dougherty PM, Yaksh TL, Miller YI. AIBP regulates TRPV1 activation in chemotherapy-induced peripheral neuropathy by controlling lipid raft dynamics and proximity to TLR4 in dorsal root ganglion neurons. Pain 2023; 164:e274-e285. [PMID: 36719418 PMCID: PMC10182209 DOI: 10.1097/j.pain.0000000000002834] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 11/21/2022] [Indexed: 02/01/2023]
Abstract
ABSTRACT Nociceptive afferent signaling evoked by inflammation and nerve injury is mediated by the opening of ligand-gated and voltage-gated receptors or channels localized to cholesterol-rich lipid raft membrane domains. Dorsal root ganglion (DRG) nociceptors express high levels of toll-like receptor 4 (TLR4), which also localize to lipid rafts. Genetic deletion or pharmacologic blocking of TLR4 diminishes pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In DRGs of mice with paclitaxel-induced CIPN, we analyzed DRG neuronal lipid rafts, expression of TLR4, activation of transient receptor potential cation channel subfamily V member 1 (TRPV1), and TLR4-TRPV1 interaction. Using proximity ligation assay, flow cytometry, and whole-mount DRG microscopy, we found that CIPN increased DRG neuronal lipid rafts and TLR4 expression. These effects were reversed by intrathecal injection of apolipoprotein A-I binding protein (AIBP), a protein that binds to TLR4 and specifically targets cholesterol depletion from TLR4-expressing cells. Chemotherapy-induced peripheral neuropathy increased TRPV1 phosphorylation, localization to neuronal lipid rafts, and proximity to TLR4. These effects were also reversed by AIBP treatment. Regulation of TRPV1-TLR4 interactions and their associated lipid rafts by AIBP covaried with the enduring reversal of mechanical allodynia otherwise observed in CIPN. In addition, AIBP reduced intracellular calcium in response to the TRPV1 agonist capsaicin, which was increased in DRG neurons from paclitaxel-treated mice and in the naïve mouse DRG neurons incubated in vitro with paclitaxel. Together, these results suggest that the assembly of nociceptive and inflammatory receptors in the environment of lipid rafts regulates nociceptive signaling in DRG neurons and that AIBP can control lipid raft-associated nociceptive processing.
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Affiliation(s)
| | - Julia Borges Paes Lemes
- Department of Anesthesiology, University of California, San Diego, La Jolla, California, USA
| | - Leonardo Gonzalez
- Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Lauriane Delay
- Department of Anesthesiology, University of California, San Diego, La Jolla, California, USA
| | | | - Jenny W. Lu
- Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | | | - Ann M. Gregus
- School of Neuroscience, Virginia Polytechnic and State University, Blacksburg, Virginia, USA
| | - Patrick M. Dougherty
- Departments of Anesthesia and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Tony L. Yaksh
- Department of Anesthesiology, University of California, San Diego, La Jolla, California, USA
| | - Yury I. Miller
- Department of Medicine, University of California, San Diego, La Jolla, California, USA
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24
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Taher MG, Mohammed MR, Al-Mahdawi MAS, Halaf NKA, Jalil AT, Alsandook T. The role of protein kinases in diabetic neuropathic pain: an update review. J Diabetes Metab Disord 2023; 22:147-154. [PMID: 37255803 PMCID: PMC10225446 DOI: 10.1007/s40200-023-01217-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 03/23/2023] [Indexed: 06/01/2023]
Abstract
Objectives Diabetic neuropathic pain (DNP) is a debilitating symptom of diabetic neuropathy which seriously impairs patient's quality of life. Currently, there is no specific therapy for DNP except for duloxetine and gabapentin that show limited utility in alleviating DNP. The present review aims to discuss the central role of protein kinases in the pathogenesis of DNP and their therapeutic modulation. Methods Scopus, PubMed, and Google scholar were searched up to January 2022 to find relevant studies with English language in which the roles of proteins kinases in DNP were examined. Results DNP is associated with hyperactivity in pain sensory neurons and therapies aim to specifically suppress redundant discharges in these neurons without affecting the activity of other sensory and motor neurons. Transient receptor potential vanilloid 1 (TRPV1) and purinergic 2 × 7 receptors (P2 × 7R) are two receptor channels, highly expressed in pain sensory neurons and their blockade produces remarkable analgesic effects in DNP. The activities of receptor channels are mainly regulated by the protein kinases whose modulation provides remarkable analgesic effects in DNP models. Conclusion Capsaicin, TRPV1 modulator, is the only agent successfully examined in clinical trials with promising effects in patients with DNP. Current data suggest that blocking calcium calmodulin dependent protein kinase II (CaMKII) is superior to other approaches, considering its pivotal role in regulating the pain neuron potentials. By this means, DNP alleviation is achievable without affecting the activity of other sensory or motor neurons.
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Affiliation(s)
- Mustafa Gheni Taher
- Department of Pathology and Forensic Medicine, College of Medicine, University of Diyala, Baquba, Diyala Iraq
| | | | | | | | - Abduladheem Turki Jalil
- Department of Medical Laboratories Techniques, Al-Mustaqbal University College, Hilla, Babylon, Iraq
| | - Tahani Alsandook
- Department of Dentistry, Al-Turath University College, Baghdad, Iraq
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25
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Baskaran P, Mohandass A, Gustafson N, Bennis J, Louis S, Alexander B, Nemenov MI, Thyagarajan B, Premkumar LS. Evaluation of a polymer-coated nanoparticle cream formulation of resiniferatoxin for the treatment of painful diabetic peripheral neuropathy. Pain 2023; 164:782-790. [PMID: 36001079 PMCID: PMC9950295 DOI: 10.1097/j.pain.0000000000002765] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/10/2022] [Indexed: 02/02/2023]
Abstract
ABSTRACT Painful diabetic peripheral neuropathy (PDPN) is one of the major complications of diabetes. Currently, centrally acting drugs and topical analgesics are used for treating PDPN. These drugs have adverse effects; some are ineffective, and treatment with opioids is associated with use dependence and addiction. Recent research indicates that transient receptor potential vanilloid 1 (TRPV1) expressed in the peripheral sensory nerve terminals is an emerging target to treat pain associated with PDPN. Block of TRPV1 ion channel with specific antagonists, although effective as an analgesic, induced hyperthermia in clinical trials. However, TRPV1 agonists are useful to treat pain by virtue of their ability to cause Ca 2+ influx and subsequently leading to nerve terminal desensitization. Here, we report the effectiveness of an ultrapotent TRPV1 agonist, resiniferatoxin (RTX) nanoparticle, in a topical formulation (RTX-cream; RESINIZIN) that alleviates pain associated with DPN in animal models of diabetes. Resiniferatoxin causes nerve terminal depolarization block in the short term, which prevents pain during application and leading to nerve terminal desensitization/depletion in the long term resulting in long-lasting pain relief. Application of RTX cream to the hind limbs suppresses thermal hyperalgesia in streptozotocin-induced diabetic rats and mini pigs without any adverse effects as compared with capsaicin at therapeutic doses, which induces intense pain during application. Resiniferatoxin cream also decreases the expression of TRPV1 in the peripheral nerve endings and suppresses TRPV1-mediated calcitonin gene-related peptide release in the skin samples of diabetic rats and mini pigs. Our preclinical data confirm that RTX topical formulation is an effective treatment option for PDPN.
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Affiliation(s)
- Padmamalini Baskaran
- School of Pharmacy, University of Wyoming, Laramie, WY, USA
- Ion Channel, Pharmacology LLC, Springfield, IL, USA
| | | | - Noah Gustafson
- School of Pharmacy, University of Wyoming, Laramie, WY, USA
| | - Jane Bennis
- School of Pharmacy, University of Wyoming, Laramie, WY, USA
| | - Somaja Louis
- Department of Pharmacology, Southern Illinois University, Springfield, IL
| | | | - Mikhail I. Nemenov
- Department of Anesthesia, Stanford University, Palo Alto, CA, USA
- LasMed LLC, Mountain View, CA, USA
| | | | - Louis S. Premkumar
- Department of Pharmacology, Southern Illinois University, Springfield, IL
- Ion Channel, Pharmacology LLC, Springfield, IL, USA
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26
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Scalable Synthesis of TRPV1 Antagonist Bipyridinyl Benzimidazole Derivative via the Suzuki-Miyaura Reaction and Selective SeO 2 Oxidation. MOLECULES (BASEL, SWITZERLAND) 2023; 28:molecules28020836. [PMID: 36677895 PMCID: PMC9860766 DOI: 10.3390/molecules28020836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/29/2022] [Accepted: 01/10/2023] [Indexed: 01/18/2023]
Abstract
In this study, a kilogram-scale synthesis of a potent TRPV1 antagonist, 1, is described. To synthesize bipyridinyl benzimidazole derivative 1, we have developed a scalable Suzuki-Miyaura reaction capable of providing a key intermediate, 6'-methyl-3-(trifluoromethyl)-2,3'-bipyridine 4, on a kilogram scale. Then, unlike the existing oxidation reaction pathway, two synthetic routes that can be applied to mass production of bipyridinyl carboxylic acid intermediate 5 or aldehyde intermediate 6 were developed by appropriately controlling the oxidation reaction using a selenium dioxide oxidizing agent. Using our developed synthetic procedure, which includes Suzuki-Miyaura coupling, selective selenium dioxide oxidation, and benzimidazole formation, multi-kilogram-scale bi-pyridinyl benzimidazole derivative 1 can be synthesized.
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27
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Spekker E, Körtési T, Vécsei L. TRP Channels: Recent Development in Translational Research and Potential Therapeutic Targets in Migraine. Int J Mol Sci 2022; 24:ijms24010700. [PMID: 36614146 PMCID: PMC9820749 DOI: 10.3390/ijms24010700] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/22/2022] [Accepted: 12/29/2022] [Indexed: 01/03/2023] Open
Abstract
Migraine is a chronic neurological disorder that affects approximately 12% of the population. The cause of migraine headaches is not yet known, however, when the trigeminal system is activated, neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) are released, which cause neurogenic inflammation and sensitization. Advances in the understanding of migraine pathophysiology have identified new potential pharmacological targets. In recent years, transient receptor potential (TRP) channels have been the focus of attention in the pathophysiology of various pain disorders, including primary headaches. Genetic and pharmacological data suggest the role of TRP channels in pain sensation and the activation and sensitization of dural afferents. In addition, TRP channels are widely expressed in the trigeminal system and brain regions which are associated with the pathophysiology of migraine and furthermore, co-localize several neuropeptides that are implicated in the development of migraine attacks. Moreover, there are several migraine trigger agents known to activate TRP channels. Based on these, TRP channels have an essential role in migraine pain and associated symptoms, such as hyperalgesia and allodynia. In this review, we discuss the role of the certain TRP channels in migraine pathophysiology and their therapeutic applicability.
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Affiliation(s)
- Eleonóra Spekker
- ELKH-SZTE Neuroscience Research Group, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
| | - Tamás Körtési
- ELKH-SZTE Neuroscience Research Group, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
- Faculty of Health Sciences and Social Studies, University of Szeged, Temesvári krt. 31, H-6726 Szeged, Hungary
| | - László Vécsei
- ELKH-SZTE Neuroscience Research Group, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
- Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
- Correspondence: ; Tel.: +36-62-545351; Fax: +36-62-545597
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28
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TRPV1: A Common Denominator Mediating Antinociceptive and Antiemetic Effects of Cannabinoids. Int J Mol Sci 2022; 23:ijms231710016. [PMID: 36077412 PMCID: PMC9456209 DOI: 10.3390/ijms231710016] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 12/19/2022] Open
Abstract
The most common medicinal claims for cannabis are relief from chronic pain, stimulation of appetite, and as an antiemetic. However, the mechanisms by which cannabis reduces pain and prevents nausea and vomiting are not fully understood. Among more than 450 constituents in cannabis, the most abundant cannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoids either directly or indirectly modulate ion channel function. Transient receptor potential vanilloid 1 (TRPV1) is an ion channel responsible for mediating several modalities of pain, and it is expressed in both the peripheral and the central pain pathways. Activation of TRPV1 in sensory neurons mediates nociception in the ascending pain pathway, while activation of TRPV1 in the central descending pain pathway, which involves the rostral ventral medulla (RVM) and the periaqueductal gray (PAG), mediates antinociception. TRPV1 channels are thought to be implicated in neuropathic/spontaneous pain perception in the setting of impaired descending antinociceptive control. Activation of TRPV1 also can cause the release of calcitonin gene-related peptide (CGRP) and other neuropeptides/neurotransmitters from the peripheral and central nerve terminals, including the vagal nerve terminal innervating the gut that forms central synapses at the nucleus tractus solitarius (NTS). One of the adverse effects of chronic cannabis use is the paradoxical cannabis-induced hyperemesis syndrome (HES), which is becoming more common, perhaps due to the wider availability of cannabis-containing products and the chronic use of products containing higher levels of cannabinoids. Although, the mechanism of HES is unknown, the effective treatment options include hot-water hydrotherapy and the topical application of capsaicin, both activate TRPV1 channels and may involve the vagal-NTS and area postrema (AP) nausea and vomiting pathway. In this review, we will delineate the activation of TRPV1 by cannabinoids and their role in the antinociceptive/nociceptive and antiemetic/emetic effects involving the peripheral, spinal, and supraspinal structures.
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29
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Gao Y, Ma R, Weng W, Zhang H, Wang Y, Guo R, Gu X, Yang Y, Yang F, Zhou A, Cheng J, Chen ZY, Zhu MX, Li Y. TRPV1 SUMOylation suppresses itch by inhibiting TRPV1 interaction with H1 receptors. Cell Rep 2022; 39:110972. [PMID: 35705043 DOI: 10.1016/j.celrep.2022.110972] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/18/2022] [Accepted: 05/24/2022] [Indexed: 11/18/2022] Open
Abstract
The molecular mechanism underlying the functional interaction between H1R and TRPV1 remains unclear. We show here that H1R directly binds to the carboxy-terminal region of TRPV1 at residues 715-725 and 736-749. Cell-penetrating peptides containing these sequences suppress histamine-induced scratching behavior in a cheek injection model. The H1R-TRPV1 binding is kept at a minimum at rest in mouse trigeminal neurons due to TRPV1 SUMOylation and it is enhanced upon histamine treatment through a transient TRPV1 deSUMOylation. The knockin of the SUMOylation-deficient TRPV1K823R mutant in mice leads to constitutive enhancement of H1R-TRPV1 binding, which exacerbates scratching behaviors induced by histamine. Conversely, SENP1 conditional knockout in sensory neurons enhances TRPV1 SUMOylation and suppresses the histamine-induced scratching response. In addition to interfering with binding, TRPV1 SUMOylation promotes H1R degradation through ubiquitination. Our work unveils the molecular mechanism of histaminergic itch by which H1R directly binds to deSUMOylated TRPV1 to facilitate the transduction of the pruritogen signal to the scratching response.
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Affiliation(s)
- Yingwei Gao
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ruining Ma
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Weiji Weng
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Heng Zhang
- Department of Biophysics and Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yingping Wang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Rongjun Guo
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiaokun Gu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yang Yang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Fan Yang
- Department of Biophysics and Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Aiwu Zhou
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jinke Cheng
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhe-Yu Chen
- Institute of Brain Science, Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Michael X Zhu
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
| | - Yong Li
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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30
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Meza RC, Ancatén-González C, Chiu CQ, Chávez AE. Transient Receptor Potential Vanilloid 1 Function at Central Synapses in Health and Disease. Front Cell Neurosci 2022; 16:864828. [PMID: 35518644 PMCID: PMC9062234 DOI: 10.3389/fncel.2022.864828] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/29/2022] [Indexed: 12/11/2022] Open
Abstract
The transient receptor potential vanilloid 1 (TRPV1), a ligand-gated nonselective cation channel, is well known for mediating heat and pain sensation in the periphery. Increasing evidence suggests that TRPV1 is also expressed at various central synapses, where it plays a role in different types of activity-dependent synaptic changes. Although its precise localizations remain a matter of debate, TRPV1 has been shown to modulate both neurotransmitter release at presynaptic terminals and synaptic efficacy in postsynaptic compartments. In addition to being required in these forms of synaptic plasticity, TRPV1 can also modify the inducibility of other types of plasticity. Here, we highlight current evidence of the potential roles for TRPV1 in regulating synaptic function in various brain regions, with an emphasis on principal mechanisms underlying TRPV1-mediated synaptic plasticity and metaplasticity. Finally, we discuss the putative contributions of TRPV1 in diverse brain disorders in order to expedite the development of next-generation therapeutic treatments.
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Affiliation(s)
- Rodrigo C Meza
- Centro Interdisciplinario de Neurociencia de Valparaíso (CINV), Instituto de Neurociencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Carlos Ancatén-González
- Centro Interdisciplinario de Neurociencia de Valparaíso (CINV), Instituto de Neurociencias, Universidad de Valparaíso, Valparaíso, Chile.,Programa de Doctorado en Ciencias, Mención Neurociencia, Universidad de Valparaíso, Valparaíso, Chile
| | - Chiayu Q Chiu
- Centro Interdisciplinario de Neurociencia de Valparaíso (CINV), Instituto de Neurociencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Andrés E Chávez
- Centro Interdisciplinario de Neurociencia de Valparaíso (CINV), Instituto de Neurociencias, Universidad de Valparaíso, Valparaíso, Chile
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31
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Behrendt M, Solinski HJ, Schmelz M, Carr R. Bradykinin-Induced Sensitization of Transient Receptor Potential Channel Melastatin 3 Calcium Responses in Mouse Nociceptive Neurons. Front Cell Neurosci 2022; 16:843225. [PMID: 35496916 PMCID: PMC9043526 DOI: 10.3389/fncel.2022.843225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 03/18/2022] [Indexed: 11/13/2022] Open
Abstract
TRPM3 is a calcium-permeable cation channel expressed in a range of sensory neurons that can be activated by heat and the endogenous steroid pregnenolone sulfate (PS). During inflammation, the expression and function of TRPM3 are both augmented in somatosensory nociceptors. However, in isolated dorsal root ganglion (DRG) neurons application of inflammatory mediators like prostaglandins and bradykinin (BK) inhibit TRPM3. Therefore, the aim of this study was to examine the effect of preceding activation of cultured 1 day old mouse DRG neurons by the inflammatory mediator BK on TRPM3-mediated calcium responses. Calcium signals were recorded using the intensity-based dye Fluo-8. We found that TRPM3-mediated calcium responses to PS were enhanced by preceding application of BK in cells that responded to BK with a calcium signal, indicating BK receptor (BKR) expression. The majority of cells that co-expressed TRPM3 and BKRs also expressed TRPV1, however, only a small fraction co-expressed TRPA1, identified by calcium responses to capsaicin and supercinnamaldehyde, respectively. Signaling and trafficking pathways responsible for sensitization of TRPM3 following BK were characterized using inhibitors of second messenger signaling cascades and exocytosis. Pharmacological blockade of protein kinase C, calcium–calmodulin-dependent protein kinase II and diacylglycerol (DAG) lipase did not affect BK-induced sensitization, but inhibition of DAG kinase did. In addition, release of calcium from intracellular stores using thapsigargin also resulted in TRPM3 sensitization. Finally, BK did not sensitize TRPM3 in the presence of exocytosis inhibitors. Collectively, we show that preceding activation of DRG neurons by BK sensitized TRPM3-mediated calcium responses to PS. Our results indicate that BKR-mediated activation of intracellular signaling pathways comprising DAG kinase, calcium and exocytosis may contribute to TRPM3 sensitization during inflammation.
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32
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Ford ZK, Reker AN, Chen S, Kadakia F, Bunk A, Davidson S. Cannabinoid Receptor 1 Expression in Human Dorsal Root Ganglia and CB13-Induced Bidirectional Modulation of Sensory Neuron Activity. FRONTIERS IN PAIN RESEARCH 2022; 2:721332. [PMID: 35295508 PMCID: PMC8915700 DOI: 10.3389/fpain.2021.721332] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 10/08/2021] [Indexed: 12/23/2022] Open
Abstract
Cannabinoid receptors have been identified as potential targets for analgesia from studies on animal physiology and behavior, and from human clinical trials. Here, we sought to improve translational understanding of the mechanisms of cannabinoid-mediated peripheral analgesia. Human lumbar dorsal root ganglia were rapidly recovered from organ donors to perform physiological and anatomical investigations into the potential for cannabinoids to mediate analgesia at the level of the peripheral nervous system. Anatomical characterization of in situ gene expression and immunoreactivity showed that 61 and 53% of human sensory neurons express the CB1 gene and receptor, respectively. Calcium influx evoked by the algogen capsaicin was measured by Fura-2AM in dissociated human sensory neurons pre-exposed to the inflammatory mediator prostaglandin E2 (PGE2) alone or together with CB13 (1 μM), a cannabinoid agonist with limited blood–brain barrier permeability. Both a higher proportion of neurons and a greater magnitude of response to capsaicin were observed after exposure to CB13, indicating cannabinoid-mediated sensitization. In contrast, membrane properties measured by patch-clamp electrophysiology demonstrated that CB13 suppressed excitability and reduced action potential discharge in PGE2-pre-incubated sensory neurons, suggesting the suppression of sensitization. This bidirectional modulation of sensory neuron activity suggests that cannabinoids may suppress overall membrane excitability while simultaneously enhancing responsivity to TRPV1-mediated stimuli. We conclude that peripherally restricted cannabinoids may have both pro- and anti-nociceptive effects in human sensory neurons.
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Affiliation(s)
- Zachary K Ford
- Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Ashlie N Reker
- Department of Anesthesiology and Pain Research Center, University of Cincinnati, College of Medicine, Cincinnati, OH, United States
| | - Sisi Chen
- Department of Anesthesiology and Pain Research Center, University of Cincinnati, College of Medicine, Cincinnati, OH, United States
| | - Feni Kadakia
- Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Alexander Bunk
- Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Steve Davidson
- Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, OH, United States.,Department of Anesthesiology and Pain Research Center, University of Cincinnati, College of Medicine, Cincinnati, OH, United States
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Scheff NN, Wall IM, Nicholson S, Williams H, Chen E, Tu NH, Dolan JC, Liu CZ, Janal MN, Bunnett NW, Schmidt BL. Oral cancer induced TRPV1 sensitization is mediated by PAR 2 signaling in primary afferent neurons innervating the cancer microenvironment. Sci Rep 2022; 12:4121. [PMID: 35260737 PMCID: PMC8904826 DOI: 10.1038/s41598-022-08005-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 02/22/2022] [Indexed: 11/29/2022] Open
Abstract
Oral cancer patients report sensitivity to spicy foods and liquids. The mechanism responsible for chemosensitivity induced by oral cancer is not known. We simulate oral cancer-induced chemosensitivity in a xenograft oral cancer mouse model using two-bottle choice drinking and conditioned place aversion assays. An anatomic basis of chemosensitivity is shown in increased expression of TRPV1 in anatomically relevant trigeminal ganglion (TG) neurons in both the xenograft and a carcinogen (4-nitroquinoline 1-oxide)-induced oral cancer mouse models. The percent of retrograde labeled TG neurons that respond to TRPV1 agonist, capsaicin, is increased along with the magnitude of response as measured by calcium influx, in neurons from the cancer models. To address the possible mechanism of TRPV1 sensitivity in tongue afferents, we study the role of PAR2, which can sensitize the TRPV1 channel. We show co-expression of TRPV1 and PAR2 on tongue afferents and using a conditioned place aversion assay, demonstrate that PAR2 mediates oral cancer-induced, TRPV1-evoked sensitivity in an oral cancer mouse model. The findings provide insight into oral cancer-mediated chemosensitivity.
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Affiliation(s)
- Nicole N Scheff
- Department of Neurobiology and Hillman Cancer Research Center, University of Pittsburgh, Pittsburgh, USA
| | - Ian M Wall
- Department of Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University (NYU) College of Dentistry, New York, USA
| | - Sam Nicholson
- Department of Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University (NYU) College of Dentistry, New York, USA
| | - Hannah Williams
- Department of Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University (NYU) College of Dentistry, New York, USA
| | - Elyssa Chen
- Department of Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University (NYU) College of Dentistry, New York, USA
| | - Nguyen H Tu
- Department of Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University (NYU) College of Dentistry, New York, USA
| | - John C Dolan
- Department of Oral and Maxillofacial Surgery, Bluestone Center for Clinical Research, New York University (NYU) College of Dentistry, New York, USA
| | - Cheng Z Liu
- Pathology Department, NYU Langone Health, New York, USA
| | - Malvin N Janal
- Department of Epidemiology and Health Promotion, NYU College of Dentistry, New York, USA
| | - Nigel W Bunnett
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, USA
- Department of Neuroscience and Physiology, Neuroscience Institute, NYU Langone Health Neuroscience Institute, NYU Langone Health, New York, USA
| | - Brian L Schmidt
- Department of Neurobiology and Hillman Cancer Research Center, University of Pittsburgh, Pittsburgh, USA.
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, USA.
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Phan TX, Ton HT, Gulyás H, Pórszász R, Tóth A, Russo R, Kay MW, Sahibzada N, Ahern GP. TRPV1 in arteries enables a rapid myogenic tone. J Physiol 2022; 600:1651-1666. [PMID: 35020949 PMCID: PMC8976781 DOI: 10.1113/jp281873] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 01/11/2022] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS We explored the physiological role of TRPV1 in vascular smooth muscle. TRPV1 antagonists dilated skeletal muscle arterioles both ex vivo and in vivo, increased coronary perfusion and decreased systemic blood pressure. Stretch of arteriolar myocytes and increases in intraluminal pressure in arteries triggered rapid Ca2+ signaling and vasoconstriction respectively. Pharmacologic and/or genetic disruption of TRPV1 significantly inhibited the magnitude and rate of these responses. Furthermore, disrupting TRPV1 blunted the rapid vasodilation evoked by arterial constriction. Pharmacological experiments identified key roles for phospholipase C and protein kinase C, combined with temperature, in TRPV1-dependent arterial tone. These results show that TRPV1 in arteriolar myocytes dynamically regulates myogenic tone and blood flow in the heart and skeletal muscle. ABSTRACT Arterioles maintain blow flow by adjusting their diameter in response to changes in local blood pressure. In this process called the myogenic response, a vascular smooth muscle mechanosensor controls tone predominantly through altering the membrane potential. In general, myogenic responses occur slowly (minutes). In the heart and skeletal muscle, however, tone is activated rapidly (tens of seconds) and terminated by brief (100 ms) arterial constrictions. Previously, we identified extensive expression of TRPV1 in the smooth muscle of arterioles supplying skeletal muscle, heart and fat. Here we reveal a critical role for TRPV1 in the rapid myogenic tone of these tissues. TRPV1 antagonists dilated skeletal muscle arterioles in vitro and in vivo, increased coronary flow in isolated hearts, and transiently decreased blood pressure. All of these pharmacologic effects were abolished by genetic disruption of TRPV1. Stretch of isolated vascular smooth muscle cells or raised intravascular pressure in arteries triggered Ca2+ signaling and vasoconstriction. The majority of these stretch-responses were TRPV1-mediated, with the remaining tone being inhibited by the TRPM4 antagonist, 9-phenantrol. Notably, tone developed more quickly in arteries from wild-type compared with TRPV1-null mice. Furthermore, the immediate vasodilation following brief constriction of arterioles depended on TRPV1, consistent with a rapid deactivation of TRPV1. Pharmacologic experiments revealed that membrane stretch activates phospholipase C/protein kinase C signaling combined with heat to activate TRPV1, and in turn, L-type Ca2+ channels. These results suggest a critical role, for TRPV1 in the dynamic regulation of myogenic tone and blood flow in the heart and skeletal muscle. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Thieu X Phan
- Department of Pharmacology and Physiology, Georgetown University, Washington, DC, USA.,Department of Biology, Vinh University, Vinh City, Vietnam
| | - Hoai T Ton
- Department of Pharmacology and Physiology, Georgetown University, Washington, DC, USA.,Department of Biology, Vinh University, Vinh City, Vietnam
| | - Hajnalka Gulyás
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Doctoral School of Pharmaceutical Sciences, Debrecen, Hungary
| | - Róbert Pórszász
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Doctoral School of Pharmaceutical Sciences, Debrecen, Hungary
| | - Attila Tóth
- Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Rebekah Russo
- Department of Biomedical Engineering, George Washington University, Washington, DC, USA
| | - Matthew W Kay
- Department of Biomedical Engineering, George Washington University, Washington, DC, USA
| | - Niaz Sahibzada
- Department of Pharmacology and Physiology, Georgetown University, Washington, DC, USA
| | - Gerard P Ahern
- Department of Pharmacology and Physiology, Georgetown University, Washington, DC, USA
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Seol SH, Chung G. Estrogen-dependent regulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3): Implication in burning mouth syndrome. J Dent Sci 2022; 17:8-13. [PMID: 35028015 PMCID: PMC8739235 DOI: 10.1016/j.jds.2021.06.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/14/2021] [Indexed: 12/20/2022] Open
Abstract
Sex differences in the nervous system have gained recent academic interest. While the prominent differences are observed in mood and anxiety disorders, growing number of evidences also suggest sex difference in pain perception. This review focuses on estrogen as the key molecule underlying such difference, because estrogen plays many functions in the nervous system, including modulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3), two important nociceptive receptors. Estrogen was shown in various studies to up-regulate TRPV1 expression through two distinct pathways, resulting in pro-nociceptive effect. However, estrogen alleviated pain in other studies, by down-regulating nerve growth factor (NGF)-activated pathways and TRPV1. Estrogen may also attenuate nociception by inhibiting P2X3 receptors and ATP-signaling. Understanding the mechanism underlying the pro- and anti-nociceptive effect of estrogen might be crucial to understand pathophysiology of the burning mouth syndrome (BMS), a common chronic orofacial pain disorder in menopausal women. The involvement of TRPV1 is strongly suspected because of burning sensation. Reduced estrogen level of the BMS patient might have caused increased activity of P2X3 receptors. Interestingly, the increased expression of TRPV1 and P2X3 in oral mucosa of BMS patients was reported. The combinational impact of differential modulation of TRPV1/P2X3 during menopause might be an important contributing factor of etiology of BMS. Understanding the estrogen-dependent regulation of nociceptive receptors may provide a valuable insight toward the peripheral mechanism of sex-difference in pain perception.
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Affiliation(s)
- Seon-Hong Seol
- College of Human Ecology, Seoul National University, Seoul, South Korea
| | - Gehoon Chung
- Department of Oral Physiology, School of Dentistry, Seoul National University, Seoul, South Korea
- Dental Research Institute, Seoul National University, Seoul, South Korea
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Nemenov MI, Singleton JR, Premkumar LS. Role of Mechanoinsensitive Nociceptors in Painful Diabetic Peripheral Neuropathy. Curr Diabetes Rev 2022; 18:e081221198649. [PMID: 34879806 DOI: 10.2174/1573399818666211208101555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 03/08/2021] [Accepted: 07/09/2021] [Indexed: 11/22/2022]
Abstract
The cutaneous mechanisms that trigger spontaneous neuropathic pain in diabetic peripheral neuropathy (PDPN) are far from clear. Two types of nociceptors are found within the epidermal and dermal skin layers. Small-diameter lightly myelinated Aδ and unmyelinated C cutaneous mechano and heat-sensitive (AMH and CMH) and C mechanoinsensitive (CMi) nociceptors transmit pain from the periphery to central nervous system. AMH and CMH fibers are mainly located in the epidermis, and CMi fibers are distributed in the dermis. In DPN, dying back intra-epidermal AMH and CMH fibers leads to reduced pain sensitivity, and the patients exhibit significantly increased pain thresholds to acute pain when tested using traditional methods. The role of CMi fibers in painful neuropathies has not been fully explored. Microneurography has been the only tool to access CMi fibers and differentiate AMH, CMH, and CMi fiber types. Due to the complexity, its use is impractical in clinical settings. In contrast, a newly developed diode laser fiber selective stimulation (DLss) technique allows to safely and selectively stimulate Aδ and C fibers in the superficial and deep skin layers. DLss data demonstrate that patients with painful DPN have increased Aδ fiber pain thresholds, while C-fiber thresholds are intact because, in these patients, CMi fibers are abnormally spontaneously active. It is also possible to determine the involvement of CMi fibers by measuring the area of DLss-induced neurogenic axon reflex flare. The differences in AMH, CMH, and CMi fibers identify patients with painful and painless neuropathy. In this review, we will discuss the role of CMi fibers in PDPN.
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Affiliation(s)
- Mikhail I Nemenov
- Department of Anesthesia, Stanford University, Palo Alto, CA, USA
- Lasmed LLC, Mountain View, CA, USA
| | | | - Louis S Premkumar
- Department of Pharmacology, SIU School of Medicine, Springfield, Illinois, USA and Ion Channel Pharmacology LLC, Springfield, IL, USA
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Spekker E, Tanaka M, Szabó Á, Vécsei L. Neurogenic Inflammation: The Participant in Migraine and Recent Advancements in Translational Research. Biomedicines 2021; 10:76. [PMID: 35052756 PMCID: PMC8773152 DOI: 10.3390/biomedicines10010076] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 12/24/2022] Open
Abstract
Migraine is a primary headache disorder characterized by a unilateral, throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors, and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses, including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This narrative review discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease.
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Affiliation(s)
- Eleonóra Spekker
- Neuroscience Research Group, Hungarian Academy of Sciences, University of Szeged (MTA-SZTE), H-6725 Szeged, Hungary; (E.S.); (M.T.)
| | - Masaru Tanaka
- Neuroscience Research Group, Hungarian Academy of Sciences, University of Szeged (MTA-SZTE), H-6725 Szeged, Hungary; (E.S.); (M.T.)
- Interdisciplinary Excellence Centre, Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, H-6725 Szeged, Hungary;
| | - Ágnes Szabó
- Interdisciplinary Excellence Centre, Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, H-6725 Szeged, Hungary;
| | - László Vécsei
- Neuroscience Research Group, Hungarian Academy of Sciences, University of Szeged (MTA-SZTE), H-6725 Szeged, Hungary; (E.S.); (M.T.)
- Interdisciplinary Excellence Centre, Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, H-6725 Szeged, Hungary;
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Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation. Cells 2021; 11:cells11010018. [PMID: 35011580 PMCID: PMC8750852 DOI: 10.3390/cells11010018] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
Capsaicin is a potent agonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1) channel and is a common component found in the fruits of the genus Capsicum plants, which have been known to humanity and consumed in food for approximately 7000-9000 years. The fruits of Capsicum plants, such as chili pepper, have been long recognized for their high nutritional value. Additionally, capsaicin itself has been proposed to exhibit vasodilatory, antimicrobial, anti-cancer, and antinociceptive properties. However, a growing body of evidence reveals a vasoconstrictory potential of capsaicin acting via the vascular TRPV1 channel and suggests that unnecessary high consumption of capsaicin may cause severe consequences, including vasospasm and myocardial infarction in people with underlying inflammatory conditions. This review focuses on vascular TRPV1 channels that are endogenously expressed in both vascular smooth muscle and endothelial cells and emphasizes the role of inflammation in sensitizing the TRPV1 channel to capsaicin activation. Tilting the balance between the beneficial vasodilatory action of capsaicin and its unwanted vasoconstrictive effects may precipitate adverse outcomes such as vasospasm and myocardial infarction, especially in the presence of proinflammatory mediators.
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Lian J, Casari I, Falasca M. Modulatory role of the endocannabinoidome in the pathophysiology of the gastrointestinal tract. Pharmacol Res 2021; 175:106025. [PMID: 34883211 DOI: 10.1016/j.phrs.2021.106025] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/29/2021] [Accepted: 12/05/2021] [Indexed: 12/13/2022]
Abstract
Originating from Eastern Asia, the plant Cannabis sativa has been used for centuries as a medicinal treatment. The unwanted psychotropic effects of one of its major components, Δ9-tetrahydrocannabinol, discouraged its therapeutic employment until, recently, the discovery of cannabinoids receptors and their endogenous ligands endocannabinoids reignited the interest. The endocannabinoid system has lately been found to play an important role in the maintenance of human health, both centrally and peripherally. However, the initial idea of the endocannabinoid system structure has been quickly understood to be too simplistic and, as new receptors, mediators, and enzymes have been discovered to participate in a complex relationship, the new, more comprehensive term "expanded endocannabinoid system" or "endocannabinoidome", has taken over. The discovery of other endocannabinoid-like receptors, such as the G protein-coupled receptor 119 and G protein-coupled receptor 55, has opened the way to the development of potential therapeutic targets for the treatment of various metabolic disorders. In addition, recent findings have also provided evidence suggesting the potential therapeutic link between the endocannabinoidome and various inflammatory-based gut diseases, such as inflammatory bowel disease and cancer. This review will provide an introduction to the endocannabinoidome, focusing on its modulatory role in the gastrointestinal tract and on the interest generated by the link between gut microbiota, the endocannabinoid system and metabolic diseases such as inflammatory bowel disease, type-2 diabetes and obesity. In addition, we will look at the potential novel aspects and benefits of drugs targeting the endocannabinoid system.
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Affiliation(s)
- Jerome Lian
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Ilaria Casari
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia.
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Go EJ, Ji J, Kim YH, Berta T, Park CK. Transient Receptor Potential Channels and Botulinum Neurotoxins in Chronic Pain. Front Mol Neurosci 2021; 14:772719. [PMID: 34776867 PMCID: PMC8586451 DOI: 10.3389/fnmol.2021.772719] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 10/11/2021] [Indexed: 12/30/2022] Open
Abstract
Pain afflicts more than 1.5 billion people worldwide, with hundreds of millions suffering from unrelieved chronic pain. Despite widespread recognition of the importance of developing better interventions for the relief of chronic pain, little is known about the mechanisms underlying this condition. However, transient receptor potential (TRP) ion channels in nociceptors have been shown to be essential players in the generation and progression of pain and have attracted the attention of several pharmaceutical companies as therapeutic targets. Unfortunately, TRP channel inhibitors have failed in clinical trials, at least in part due to their thermoregulatory function. Botulinum neurotoxins (BoNTs) have emerged as novel and safe pain therapeutics because of their regulation of exocytosis and pro-nociceptive neurotransmitters. However, it is becoming evident that BoNTs also regulate the expression and function of TRP channels, which may explain their analgesic effects. Here, we summarize the roles of TRP channels in pain, with a particular focus on TRPV1 and TRPA1, their regulation by BoNTs, and briefly discuss the use of BoNTs for the treatment of chronic pain.
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Affiliation(s)
- Eun Jin Go
- Department of Physiology, Gachon Pain Center, Gachon University College of Medicine, Incheon, South Korea
| | - Jeongkyu Ji
- Gachon University College of Medicine, Incheon, South Korea
| | - Yong Ho Kim
- Department of Physiology, Gachon Pain Center, Gachon University College of Medicine, Incheon, South Korea
| | - Temugin Berta
- Department of Anesthesiology, Pain Research Center, University of Cincinnati Medical Center, Cincinnati, OH, United States
| | - Chul-Kyu Park
- Department of Physiology, Gachon Pain Center, Gachon University College of Medicine, Incheon, South Korea
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Liviero F, Campisi M, Mason P, Pavanello S. Transient Receptor Potential Vanilloid Subtype 1: Potential Role in Infection, Susceptibility, Symptoms and Treatment of COVID-19. Front Med (Lausanne) 2021; 8:753819. [PMID: 34805220 PMCID: PMC8599155 DOI: 10.3389/fmed.2021.753819] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 10/08/2021] [Indexed: 12/20/2022] Open
Abstract
The battle against the new coronavirus that continues to kill millions of people will be still long. Novel strategies are demanded to control infection, mitigate symptoms and treatment of COVID-19. This is even more imperative given the long sequels that the disease has on the health of the infected. The discovery that S protein includes two ankyrin binding motifs (S-ARBMs) and that the transient receptor potential vanilloid subtype 1 (TRPV-1) cation channels contain these ankyrin repeat domains (TRPs-ARDs) suggest that TRPV-1, the most studied member of the TRPV channel family, can play a role in binding SARS-CoV-2. This hypothesis is strengthened by studies showing that other respiratory viruses bind the TRPV-1 on sensory nerves and epithelial cells in the airways. Furthermore, the pathophysiology in COVID-19 patients is similar to the effects generated by TRPV-1 stimulation. Lastly, treatment with agonists that down-regulate or inactivate TRPV-1 can have a beneficial action on impaired lung functions and clearance of infection. In this review, we explore the role of the TRPV-1 channel in the infection, susceptibility, pathogenesis, and treatment of COVID-19, with the aim of looking at novel strategies to control infection and mitigate symptoms, and trying to translate this knowledge into new preventive and therapeutic interventions.
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Affiliation(s)
| | | | | | - Sofia Pavanello
- Occupational Medicine, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University Hospital of Padua, Padova, Italy
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Luu DD, Owens AM, Mebrat MD, Van Horn WD. A molecular perspective on identifying TRPV1 thermosensitive regions and disentangling polymodal activation. Temperature (Austin) 2021; 10:67-101. [PMID: 37187836 PMCID: PMC10177694 DOI: 10.1080/23328940.2021.1983354] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 09/10/2021] [Accepted: 09/16/2021] [Indexed: 10/20/2022] Open
Abstract
TRPV1 is a polymodal receptor ion channel that is best known to function as a molecular thermometer. It is activated in diverse ways, including by heat, protons (low pH), and vanilloid compounds, such as capsaicin. In this review, we summarize molecular studies of TRPV1 thermosensing, focusing on the cross-talk between heat and other activation modes. Additional insights from TRPV1 isoforms and non-rodent/non-human TRPV1 ortholog studies are also discussed in this context. While the molecular mechanism of heat activation is still emerging, it is clear that TRPV1 thermosensing is modulated allosterically, i.e., at a distance, with contributions from many distinct regions of the channel. Similarly, current studies identify cross-talk between heat and other TRPV1 activation modes, such as protons and capsaicin, and that these modes can generally be selectively disentangled. In aggregate, this suggests that future TRPV1 molecular studies should define allosteric pathways and provide mechanistic insight, thereby enabling mode-selective manipulation of the polymodal receptor. These advances are anticipated to have significant implications in both basic and applied biomedical sciences.
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Affiliation(s)
- Dustin D. Luu
- School of Molecular Sciences, Arizona State University, Tempe, Arizona, USA
- The Biodesign Institute Virginia G. Piper Center for Personalized Diagnostics,Arizona State University, Tempe, Arizona,USA
| | - Aerial M. Owens
- School of Molecular Sciences, Arizona State University, Tempe, Arizona, USA
- The Biodesign Institute Virginia G. Piper Center for Personalized Diagnostics,Arizona State University, Tempe, Arizona,USA
| | - Mubark D. Mebrat
- School of Molecular Sciences, Arizona State University, Tempe, Arizona, USA
- The Biodesign Institute Virginia G. Piper Center for Personalized Diagnostics,Arizona State University, Tempe, Arizona,USA
| | - Wade D. Van Horn
- School of Molecular Sciences, Arizona State University, Tempe, Arizona, USA
- The Biodesign Institute Virginia G. Piper Center for Personalized Diagnostics,Arizona State University, Tempe, Arizona,USA
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Palmaers NE, Wiegand SB, Herzog C, Echtermeyer FG, Eberhardt MJ, Leffler A. Distinct Mechanisms Account for In Vitro Activation and Sensitization of TRPV1 by the Porphyrin Hemin. Int J Mol Sci 2021; 22:ijms221910856. [PMID: 34639197 PMCID: PMC8509749 DOI: 10.3390/ijms221910856] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/03/2021] [Accepted: 10/04/2021] [Indexed: 12/02/2022] Open
Abstract
TRPV1 mediates pain occurring during sickling episodes in sickle cell disease (SCD). We examined if hemin, a porphyrin released during intravascular hemolysis modulates TRPV1. Calcium imaging and patch clamp were employed to examine effects of hemin on mouse dorsal root ganglion (DRG) neurons and HEK293t cells expressing TRPV1 and TRPA1. Hemin induced a concentration-dependent calcium influx in DRG neurons which was abolished by the unspecific TRP-channel inhibitor ruthenium red. The selective TRPV1-inhibitor BCTC or genetic deletion of TRPV1 only marginally impaired hemin-induced calcium influx in DRG neurons. While hTRPV1 expressed in HEK293 cells mediated a hemin-induced calcium influx which was blocked by BCTC, patch clamp recordings only showed potentiated proton- and heat-evoked currents. This effect was abolished by the PKC-inhibitor chelerythrine chloride and in protein kinase C (PKC)-insensitive TRPV1-mutants. Hemin-induced calcium influx through TRPV1 was only partly PKC-sensitive, but it was abolished by the reducing agent dithiothreitol (DTT). In contrast, hemin-induced potentiation of inward currents was not reduced by DTT. Hemin also induced a redox-dependent calcium influx, but not inward currents on hTRPA1. Our data suggest that hemin induces a PKC-mediated sensitization of TRPV1. However, it also acts as a photosensitizer when exposed to UVA-light used for calcium imaging. The resulting activation of redox-sensitive ion channels such as TRPV1 and TRPA1 may be an in vitro artifact with limited physiological relevance.
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Biringer RG. A review of non-prostanoid, eicosanoid receptors: expression, characterization, regulation, and mechanism of action. J Cell Commun Signal 2021; 16:5-46. [PMID: 34173964 DOI: 10.1007/s12079-021-00630-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 06/07/2021] [Indexed: 11/29/2022] Open
Abstract
Eicosanoid signaling controls a wide range of biological processes from blood pressure homeostasis to inflammation and resolution thereof to the perception of pain and to cell survival itself. Disruption of normal eicosanoid signaling is implicated in numerous disease states. Eicosanoid signaling is facilitated by G-protein-coupled, eicosanoid-specific receptors and the array of associated G-proteins. This review focuses on the expression, characterization, regulation, and mechanism of action of non-prostanoid, eicosanoid receptors.
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Affiliation(s)
- Roger G Biringer
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, 5000 Lakewood Ranch Blvd, Bradenton, FL, 34211, USA.
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Cao E. Structural mechanisms of transient receptor potential ion channels. J Gen Physiol 2021; 152:133640. [PMID: 31972006 PMCID: PMC7054860 DOI: 10.1085/jgp.201811998] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 01/03/2020] [Indexed: 12/26/2022] Open
Abstract
Transient receptor potential (TRP) ion channels are evolutionarily ancient sensory proteins that detect and integrate a wide range of physical and chemical stimuli. TRP channels are fundamental for numerous biological processes and are therefore associated with a multitude of inherited and acquired human disorders. In contrast to many other major ion channel families, high-resolution structures of TRP channels were not available before 2013. Remarkably, however, the subsequent “resolution revolution” in cryo-EM has led to an explosion of TRP structures in the last few years. These structures have confirmed that TRP channels assemble as tetramers and resemble voltage-gated ion channels in their overall architecture. But beyond the relatively conserved transmembrane core embedded within the lipid bilayer, each TRP subtype appears to be endowed with a unique set of soluble domains that may confer diverse regulatory mechanisms. Importantly, TRP channel structures have revealed sites and mechanisms of action of numerous synthetic and natural compounds, as well as those for endogenous ligands such as lipids, Ca2+, and calmodulin. Here, I discuss these recent findings with a particular focus on the conserved transmembrane region and how these structures may help to rationally target this important class of ion channels for the treatment of numerous human conditions.
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Affiliation(s)
- Erhu Cao
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT
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Gladkikh IN, Sintsova OV, Leychenko EV, Kozlov SA. TRPV1 Ion Channel: Structural Features, Activity Modulators, and Therapeutic Potential. BIOCHEMISTRY (MOSCOW) 2021; 86:S50-S70. [PMID: 33827400 DOI: 10.1134/s0006297921140054] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Although TRPV1 ion channel has been attracting researchers' attention for many years, its functions in animal organisms, the principles of regulation, and the involvement in pathological processes have not yet been fully clarified. Mutagenesis experiments and structural studies have identified the structural features of the channel and binding sites for its numerous ligands; however, these studies are far from conclusion. This review summarizes recent achievements in the TRPV1 research with special focus on structural and functional studies of the channel and on its ligands, which are extremely diverse in their nature and interaction specificity to TRPV1. Particular attention was given to the effects of numerous endogenous agonists and antagonists that can fine-tune the channel sensitivity to its usual activators, such as capsaicin, heat, acids, or their combination. In addition to the pain sensing not covered in this review, the TRPV1 channel was found to be involved in the regulation of many important physiological and pathological processes and, therefore, can be considered as a promising therapeutic target in the treatment of various diseases, such as pneumonia, ischemia, diabetes, epilepsy, schizophrenia, psoriasis, etc.
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Affiliation(s)
- Irina N Gladkikh
- Elyakov Pacific Institute of Bioorganic Chemistry, Far East Branch of the Russian Academy of Sciences, Vladivostok, 690022, Russia
| | - Oksana V Sintsova
- Elyakov Pacific Institute of Bioorganic Chemistry, Far East Branch of the Russian Academy of Sciences, Vladivostok, 690022, Russia
| | - Elena V Leychenko
- Elyakov Pacific Institute of Bioorganic Chemistry, Far East Branch of the Russian Academy of Sciences, Vladivostok, 690022, Russia
| | - Sergey A Kozlov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia.
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Takahashi K, Araki K, Miyamoto H, Shirakawa R, Yoshida T, Wakamori M. Capsaicin and Proton Differently Modulate Activation Kinetics of Mouse Transient Receptor Potential Vanilloid-1 Channel Induced by Depolarization. Front Pharmacol 2021; 12:672157. [PMID: 34093200 PMCID: PMC8172580 DOI: 10.3389/fphar.2021.672157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/26/2021] [Indexed: 11/26/2022] Open
Abstract
The transient receptor potential vanilloid type 1 (TRPV1) channel is a non-selective cation channel expressed with transient receptor potential ankyrin type 1 (TRPA1) in small and medial size neurons of the dorsal root ganglions and trigeminal ganglions. TRPV1 is activated by capsaicin, thermal stimuli higher than 43°C, mechanical stress, and protons (H+). Although the TRPV1 channel does not have positively charged residues at regular intervals on its transmembrane segments, alterations in membrane potential also affect the state of TRPV1 channel. In the presence of capsaicin, voltage-dependent probability of opening of the TRPV1 channel and its kinetics have been examined, but the characteristics in the low pH remain unclear. To understand the voltage-dependency of the TRPV1 channel activation, we recorded capsaicin- and proton-induced mouse TRPV1 channel currents in a heterologous expression system. Outward current evoked by depolarizing square pulses in the presence of capsaicin or protons was fitted to a two-exponential function with a time-independent component. The voltage-dependent changes in amplitude of the three components displayed shallow curves and the changes in their ratio to the total current display similar tendencies in the presence of capsaicin and under the low pH. However, the fast and slow time constants in the presence of capsaicin were respectively 5- and 8-fold lower than those obtained under low pH conditions. These results suggest that the TRPV1 channel slowly drives the feed-forward cycle of pain sensation, and capsaicin and protons differently modulate the voltage-dependent TRPV1 channel gating.
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Affiliation(s)
- Kaori Takahashi
- Division of Molecular Pharmacology and Cell Biophysics, Department of Disease Management Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan
| | - Kentaro Araki
- Division of Molecular Pharmacology and Cell Biophysics, Department of Disease Management Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan
| | - Hideo Miyamoto
- Division of Molecular Pharmacology and Cell Biophysics, Department of Disease Management Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan
| | - Rikimaru Shirakawa
- Division of Molecular Pharmacology and Cell Biophysics, Department of Disease Management Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan
| | - Takashi Yoshida
- Division of Molecular Pharmacology and Cell Biophysics, Department of Disease Management Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan.,Division of Pharmacology, Faculty of Pharmaceutical Science, Teikyo Heisei University, Tokyo, Japan
| | - Minoru Wakamori
- Division of Molecular Pharmacology and Cell Biophysics, Department of Disease Management Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan
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Abstract
The chronification of pain can be attributed to changes in membrane receptors and channels underlying neuronal plasticity and signal transduction largely within nociceptive neurons that initiate and maintain pathological pain states. These proteins are subject to dynamic modification by posttranslational modifications, creating a code that controls protein function in time and space. Phosphorylation is an important posttranslational modification that affects ∼30% of proteins in vivo. Increased phosphorylation of various nociceptive ion channels and of their modulators underlies sensitization of different pain states. Cyclin-dependent kinases are proline-directed serine/threonine kinases that impact various biological and cellular systems. Cyclin-dependent kinase 5 (Cdk5), one member of this kinase family, and its activators p35 and p39 are expressed in spinal nerves, dorsal root ganglia, and the dorsal horn of the spinal cord. In neuropathic pain conditions, expression and/or activity of Cdk5 is increased, implicating Cdk5 in nociception. Experimental evidence suggests that Cdk5 is regulated through its own phosphorylation, through increasing p35's interaction with Cdk5, and through cleavage of p35 into p25. This narrative review discusses the molecular mechanisms of Cdk5-mediated regulation of target proteins involved in neuropathic pain. We focus on Cdk5 substrates that have been linked to nociceptive pathways, including channels (eg, transient receptor potential cation channel and voltage-gated calcium channel), proteins involved in neurotransmitter release (eg, synaptophysin and collapsin response mediator protein 2), and receptors (eg, glutamate, purinergic, and opioid). By altering the phosphoregulatory "set point" of proteins involved in pain signaling, Cdk5 thus appears to be an attractive target for treating neuropathic pain conditions.
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McMillan H, Lundy FT, Dunne OM, Al-Natour B, Jeanneau C, About I, Curtis TM, El Karim I. Endogenous Mas-related G-protein-coupled receptor X1 activates and sensitizes TRPA1 in a human model of peripheral nerves. FASEB J 2021; 35:e21492. [PMID: 33788969 DOI: 10.1096/fj.202001667rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 02/16/2021] [Accepted: 02/16/2021] [Indexed: 12/21/2022]
Abstract
Mas-related G-protein-coupled receptor X1 (MrgprX1) is a human-specific Mrgpr and its expression is restricted to primary sensory neurons. However, its role in nociception and pain signaling pathways is largely unknown. This study aims to investigate a role for MrgprX1 in nociception via interaction with the pain receptor, Transient Receptor Potential Ankyrin 1 (TRPA1), using in-vitro and in-vivo human neuronal models. MrgprX1 protein expression in human trigeminal nociceptors was investigated by the immunolabeling of the dental pulp and cultured peripheral neuronal equivalent (PNE) cells. MrgprX1 receptor signaling was monitored by Fura-2-based Ca2+ imaging using PNEs and membrane potential responses were measured using FluoVoltTM . Immunofluorescent staining revealed MrgprX1 expression in-vivo in dental afferents, which was more intense in inflamed compared to healthy dental pulps. Endogenous MrgprX1 protein expression was confirmed in the in-vitro human PNE model. MrgprX1 receptor signaling and the mechanisms through which it couples to TRPA1 were studied by Ca2+ imaging. Results showed that MrgprX1 activates TRPA1 and induces membrane depolarization in a TRPA1 dependent manner. In addition, MrgprX1 sensitizes TRPA1 to agonist stimulation via Protein Kinase C (PKC). The activation and sensitization of TRPA1 by MrgprX1 in a model of human nerves suggests an important role for this receptor in the modulation of nociception.
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Affiliation(s)
- Hayley McMillan
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, UK
| | - Fionnuala T Lundy
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, UK
| | - Orla M Dunne
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, UK
| | - Banan Al-Natour
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, UK
- Department of Oral Medicine and Oral Surgery, Faculty of Dentistry, Jordan University of Science and Technology, Irbid, Jordan
| | | | - Imad About
- Aix Marseille Univ, CNRS, ISM, Inst Movement Sci, Marseille, France
| | - Tim M Curtis
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, UK
| | - Ikhlas El Karim
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, UK
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50
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Gu Q, Lee LY. TRP channels in airway sensory nerves. Neurosci Lett 2021; 748:135719. [PMID: 33587987 PMCID: PMC7988689 DOI: 10.1016/j.neulet.2021.135719] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/01/2021] [Accepted: 02/03/2021] [Indexed: 12/12/2022]
Abstract
Transient Receptor Potential (TRP) channels expressed in specific subsets of airway sensory nerves function as transducers and integrators of a diverse range of sensory inputs including chemical, mechanical and thermal signals. These TRP sensors can detect inhaled irritants as well as endogenously released chemical substances. They play an important role in generating the afferent activity carried by these sensory nerves and regulating the centrally mediated pulmonary defense reflexes. Increasing evidence reported in recent investigations has revealed important involvements of several TRP channels (TRPA1, TRPV1, TRPV4 and TRPM8) in the manifestation of various symptoms and pathogenesis of certain acute and chronic airway diseases. This mini-review focuses primarily on these recent findings of the responses of these TRP sensors to the biological stresses emerging under the pathophysiological conditions of the lung and airways.
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Affiliation(s)
- Qihai Gu
- Department of Biomedical Sciences, Mercer University School of Medicine, 1501 Mercer University Drive, Macon, GA, 31207, USA.
| | - Lu-Yuan Lee
- Department of Physiology, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY, 40536-0298, USA.
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