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Sabater-Gárriz Á, Cerón JJ, Montoya P, Riquelme I. Potential use of salivary TNF-α as a vaccine-induced pain biomarker in people with cerebral palsy and communication disorders. PLoS One 2024; 19:e0308386. [PMID: 39729404 DOI: 10.1371/journal.pone.0308386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 07/23/2024] [Indexed: 12/29/2024] Open
Abstract
BACKGROUND Pain in people with cerebral palsy (CP) has been classically underestimated and poorly treated, particularly in individuals with impaired communication skills. OBJECTIVE To analyze changes in different salivary metabolites and pain behavior scales after a painful procedure in adults with CP and adults with typical development. METHODS Salivary levels of sTNF-α, sIgA, Cortisol, FRAP, ADA and Alpha Amylase, as well as 3 observational pain scales (Wong-Baker, Non-Communicating Adults Pain Checklist and Facial Action Coding System) were assessed before and after an intramuscular injection in 30 Individuals with CP and 30 healthy controls. Video recording of face expression was performed during the procedure for offline analysis. RESULTS Pain in subjects with CP was higher than in healthy controls after the intramuscular injection as displayed by observational scales. sTNF-α experienced a significant post-stimulus increase in both groups and that increase shows a tendency to correlate with the observational scales scores. Other biomarkers classically associated with stress (cortisol, Alpha Amylase) remain stable. CONCLUSION sTNF-α might be a promising pain indicator. Further research using controlled painful stimuli of greater intensity and pain self-reports, would be necessary to better understand its use as a pain biomarker.
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Affiliation(s)
- Álvaro Sabater-Gárriz
- Balearic ASPACE Foundation, Marratxí, Spain
- Research Institute on Health Sciences (IUNICS-IdISBa), University of the Balearic Islands, Palma de Mallorca, Spain
- Department of Nursing and Physiotherapy, University of the Balearic Islands, Palma de Mallorca, Spain
| | - José Joaquín Cerón
- Interdisciplinary Laboratory of Clinical Analysis, Interlab-UMU, Regional Campus of International Excellence Campus Mare Nostrum, University of Murcia, Murcia, Spain
| | - Pedro Montoya
- Research Institute on Health Sciences (IUNICS-IdISBa), University of the Balearic Islands, Palma de Mallorca, Spain
| | - Inmaculada Riquelme
- Research Institute on Health Sciences (IUNICS-IdISBa), University of the Balearic Islands, Palma de Mallorca, Spain
- Department of Nursing and Physiotherapy, University of the Balearic Islands, Palma de Mallorca, Spain
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Cantón-Habas V, Rich-Ruiz M, Martínez-Martos JM, Ramírez-Expósito MJ, Carrera-González MP. Determination of soluble tumor necrosis factor receptor II and secretory immunoglobulin A in saliva of patients with dementia. Eur Arch Psychiatry Clin Neurosci 2024; 274:1689-1696. [PMID: 37838644 DOI: 10.1007/s00406-023-01693-9] [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: 06/02/2023] [Accepted: 09/20/2023] [Indexed: 10/16/2023]
Abstract
The prevalence of pain and dementia increases with age, affecting a significant percentage of the population due to aging. Both pathologies are connected through the inflammatory process, specifically through the tumor necrosis factor. The effect of this cytokine is mediated through the modulation of its TNFRI and TNFRII receptors, which are linked to the dementia process. In addition, immunoglobulins such as secretory immunoglobulin A (sIgA) have been recognized as one of the main biomarkers of pain in saliva. sTNFRII and sIgA levels were determined in saliva samples by ELISA from healthy people and patients with dementia in GDS stages 5-7. The concentrations of these markers were also correlated with the GDS stage and sex. We observed a significant decrease (*** p ≤ 0.001) in the levels of sTNFRII (pg/mL) and a significant increase (** p ≤ 0.01) in the levels of sIgA (ng/mL) in the saliva of patients with dementia compared to the healthy control group. We did not observe a correlation with the data of the biomarkers regarding the GDS stage and sex. The results obtained for sTNFRII are consistent with those obtained by other authors on brain tissue, who conclude that unopposed neuronal TNFRI signaling, when TNFRII is selectively downregulated, leads to a more severe course of AD pathogenesis. Regarding sIgA, the elevated values of sIgA may reflect the immune status of these patients. Therefore, these biomarkers can provide us with relevant information through a non-invasive method such as saliva analysis.
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Affiliation(s)
- V Cantón-Habas
- Department of Nursing, Pharmacology and Physiotherapy, Faculty of Medicine and Nursing, University of Córdoba, Maimonides Institute of Biomedical Research of Córdoba (IMIBIC) IMIBIC Building, Reina, Sofia University Hospital, Av. Menéndez Pidal, s/n, 14004, Córdoba, Spain
| | - M Rich-Ruiz
- Department of Nursing, Pharmacology and Physiotherapy, Faculty of Medicine and Nursing, University of Córdoba, Maimonides Institute of Biomedical Research of Córdoba (IMIBIC) IMIBIC Building, Reina, Sofia University Hospital, Av. Menéndez Pidal, s/n, 14004, Córdoba, Spain
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain
| | - J M Martínez-Martos
- Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, Faculty of Health Sciences, University of Jaén, Campus Universitario Las Lagunillas, 23071, Jaén, Spain
| | - M J Ramírez-Expósito
- Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, Faculty of Health Sciences, University of Jaén, Campus Universitario Las Lagunillas, 23071, Jaén, Spain
| | - M P Carrera-González
- Department of Nursing, Pharmacology and Physiotherapy, Faculty of Medicine and Nursing, University of Córdoba, Maimonides Institute of Biomedical Research of Córdoba (IMIBIC) IMIBIC Building, Reina, Sofia University Hospital, Av. Menéndez Pidal, s/n, 14004, Córdoba, Spain.
- Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, Faculty of Health Sciences, University of Jaén, Campus Universitario Las Lagunillas, 23071, Jaén, Spain.
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Aguilar-Cazares D, Chavez-Dominguez R, Marroquin-Muciño M, Perez-Medina M, Benito-Lopez JJ, Camarena A, Rumbo-Nava U, Lopez-Gonzalez JS. The systemic-level repercussions of cancer-associated inflammation mediators produced in the tumor microenvironment. Front Endocrinol (Lausanne) 2022; 13:929572. [PMID: 36072935 PMCID: PMC9441602 DOI: 10.3389/fendo.2022.929572] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 08/01/2022] [Indexed: 12/15/2022] Open
Abstract
The tumor microenvironment is a dynamic, complex, and redundant network of interactions between tumor, immune, and stromal cells. In this intricate environment, cells communicate through membrane-membrane, ligand-receptor, exosome, soluble factors, and transporter interactions that govern cell fate. These interactions activate the diverse and superfluous signaling pathways involved in tumor promotion and progression and induce subtle changes in the functional activity of infiltrating immune cells. The immune response participates as a selective pressure in tumor development. In the early stages of tumor development, the immune response exerts anti-tumor activity, whereas during the advanced stages, the tumor establishes mechanisms to evade the immune response, eliciting a chronic inflammation process that shows a pro-tumor effect. The deregulated inflammatory state, in addition to acting locally, also triggers systemic inflammation that has repercussions in various organs and tissues that are distant from the tumor site, causing the emergence of various symptoms designated as paraneoplastic syndromes, which compromise the response to treatment, quality of life, and survival of cancer patients. Considering the tumor-host relationship as an integral and dynamic biological system, the chronic inflammation generated by the tumor is a communication mechanism among tissues and organs that is primarily orchestrated through different signals, such as cytokines, chemokines, growth factors, and exosomes, to provide the tumor with energetic components that allow it to continue proliferating. In this review, we aim to provide a succinct overview of the involvement of cancer-related inflammation at the local and systemic level throughout tumor development and the emergence of some paraneoplastic syndromes and their main clinical manifestations. In addition, the involvement of these signals throughout tumor development will be discussed based on the physiological/biological activities of innate and adaptive immune cells. These cellular interactions require a metabolic reprogramming program for the full activation of the various cells; thus, these requirements and the by-products released into the microenvironment will be considered. In addition, the systemic impact of cancer-related proinflammatory cytokines on the liver-as a critical organ that produces the leading inflammatory markers described to date-will be summarized. Finally, the contribution of cancer-related inflammation to the development of two paraneoplastic syndromes, myelopoiesis and cachexia, will be discussed.
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Affiliation(s)
- Dolores Aguilar-Cazares
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Mexico
| | - Rodolfo Chavez-Dominguez
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Mexico
- Posgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
| | - Mario Marroquin-Muciño
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Mexico
- Laboratorio de Quimioterapia Experimental, Departamento de Bioquimica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Mexico City, Mexico
| | - Mario Perez-Medina
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Mexico
- Laboratorio de Quimioterapia Experimental, Departamento de Bioquimica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Mexico City, Mexico
| | - Jesus J. Benito-Lopez
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Mexico
- Posgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
| | - Angel Camarena
- Laboratorio de Human Leukocyte Antigen (HLA), Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Mexico
| | - Uriel Rumbo-Nava
- Clinica de Neumo-Oncologia, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Mexico
| | - Jose S. Lopez-Gonzalez
- Laboratorio de Investigacion en Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Mexico
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Li H, Page AJ. Altered Vagal Signaling and Its Pathophysiological Roles in Functional Dyspepsia. Front Neurosci 2022; 16:858612. [PMID: 35527812 PMCID: PMC9072791 DOI: 10.3389/fnins.2022.858612] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/28/2022] [Indexed: 11/20/2022] Open
Abstract
The vagus nerve is crucial in the bidirectional communication between the gut and the brain. It is involved in the modulation of a variety of gut and brain functions. Human studies indicate that the descending vagal signaling from the brain is impaired in functional dyspepsia. Growing evidence indicate that the vagal signaling from gut to brain may also be altered, due to the alteration of a variety of gut signals identified in this disorder. The pathophysiological roles of vagal signaling in functional dyspepsia is still largely unknown, although some studies suggested it may contribute to reduced food intake and gastric motility, increased psychological disorders and pain sensation, nausea and vomiting. Understanding the alteration in vagal signaling and its pathophysiological roles in functional dyspepsia may provide information for new potential therapeutic treatments of this disorder. In this review, we summarize and speculate possible alterations in vagal gut-to-brain and brain-to-gut signaling and the potential pathophysiological roles in functional dyspepsia.
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Affiliation(s)
- Hui Li
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
- Nutrition, Diabetes and Gut Health, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- *Correspondence: Hui Li,
| | - Amanda J. Page
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
- Nutrition, Diabetes and Gut Health, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
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TNF-α-Mediated RIPK1 Pathway Participates in the Development of Trigeminal Neuropathic Pain in Rats. Int J Mol Sci 2022; 23:ijms23010506. [PMID: 35008931 PMCID: PMC8745573 DOI: 10.3390/ijms23010506] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 01/05/2023] Open
Abstract
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) participates in the regulation of cellular stress and inflammatory responses, but its function in neuropathic pain remains poorly understood. This study evaluated the role of RIPK1 in neuropathic pain following inferior alveolar nerve injury. We developed a model using malpositioned dental implants in male Sprague Dawley rats. This model resulted in significant mechanical allodynia and upregulated RIPK1 expression in the trigeminal subnucleus caudalis (TSC). The intracisternal administration of Necrosatin-1 (Nec-1), an RIPK1 inhibitor, blocked the mechanical allodynia produced by inferior alveolar nerve injury The intracisternal administration of recombinant rat tumor necrosis factor-α (rrTNF-α) protein in naive rats produced mechanical allodynia and upregulated RIPK1 expression in the TSC. Moreover, an intracisternal pretreatment with Nec-1 inhibited the mechanical allodynia produced by rrTNF-α protein. Nerve injury caused elevated TNF-α concentration in the TSC and a TNF-α block had anti-allodynic effects, thereby attenuating RIPK1 expression in the TSC. Finally, double immunofluorescence analyses revealed the colocalization of TNF receptor and RIPK1 with astrocytes. Hence, we have identified that astroglial RIPK1, activated by the TNF-α pathway, is a central driver of neuropathic pain and that the TNF-α-mediated RIPK1 pathway is a potential therapeutic target for reducing neuropathic pain following nerve injury.
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Duitama M, Moreno Y, Santander SP, Casas Z, Sutachan JJ, Torres YP, Albarracín SL. TRP Channels as Molecular Targets to Relieve Cancer Pain. Biomolecules 2021; 12:1. [PMID: 35053150 PMCID: PMC8774023 DOI: 10.3390/biom12010001] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/17/2021] [Accepted: 11/23/2021] [Indexed: 12/13/2022] Open
Abstract
Transient receptor potential (TRP) channels are critical receptors in the transduction of nociceptive stimuli. The microenvironment of diverse types of cancer releases substances, including growth factors, neurotransmitters, and inflammatory mediators, which modulate the activity of TRPs through the regulation of intracellular signaling pathways. The modulation of TRP channels is associated with the peripheral sensitization observed in patients with cancer, which results in mild noxious sensory stimuli being perceived as hyperalgesia and allodynia. Secondary metabolites derived from plant extracts can induce the activation, blocking, and desensitization of TRP channels. Thus, these compounds could act as potential therapeutic agents, as their antinociceptive properties could be beneficial in relieving cancer-derived pain. In this review, we will summarize the role of TRPV1 and TRPA1 in pain associated with cancer and discuss molecules that have been reported to modulate these channels, focusing particularly on the mechanisms of channel activation associated with molecules released in the tumor microenvironment.
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Affiliation(s)
- Milena Duitama
- Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; (M.D.); (Z.C.); (J.J.S.)
| | - Yurany Moreno
- Department of Lymphoma & Myeloma, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA;
| | - Sandra Paola Santander
- Phytoimmunomodulation Research Group, Juan N. Corpas University Foundation, Bogotá 111111, Colombia;
| | - Zulma Casas
- Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; (M.D.); (Z.C.); (J.J.S.)
| | - Jhon Jairo Sutachan
- Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; (M.D.); (Z.C.); (J.J.S.)
| | - Yolima P. Torres
- Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; (M.D.); (Z.C.); (J.J.S.)
| | - Sonia L. Albarracín
- Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana, Bogotá 110231, Colombia; (M.D.); (Z.C.); (J.J.S.)
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Tang L, Chen JR. The Predictive Value of Hemocytometry Based on Peripheral Platelet-Related Parameters in Identifying the Causes of Febrile Seizures. J Inflamm Res 2021; 14:5381-5392. [PMID: 34703275 PMCID: PMC8536886 DOI: 10.2147/jir.s334165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 09/28/2021] [Indexed: 01/12/2023] Open
Abstract
Objective To evaluate the outcome of platelet-related parameters in children with febrile seizures (FSs) and seek low-cost markers for the clinical prediction of FSs. Methods A total of 79 patients with FSs (the FS group) who were hospitalized in our hospital were selected. Eighty-two patients with fever and without seizures (the FC group) and 81 healthy patients without fever (the HC group) were selected. The results of whole blood cell analysis were retrospectively analyzed. Results The results of whole blood cell analysis showed that platelet (PLT) count, mean platelet volume (MPV), hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and hematocrit (HCT) levels in the FS group were significantly lower than in the FC and HC groups (P < 0.05). The platelet-to-lymphocyte ratio (PLR) in the FS and FC groups was significantly higher than in the HC group (P < 0.05), but there was no statistical difference between the FS and FC groups (P > 0.05). The PLT count in the CFS group was significantly lower than in the SFS group (P < 0.05). The PDW of the CFS group was higher compared with the SFS group (P < 0.05). The PLT count and PLR of the relapsed group were lower than those of the non-relapsed group (P < 0.05). The conducted linear regression analysis showed that MCH, PLT, and MPV were closely related to the occurrence of FSs. The binary logistic model showed that MPV was the most important protective factor related to FSs. Conclusion PLT and MPV are closely related to the occurrence of FSs. PLT and PDW may be able to serve as simple yet effective laboratory indicators for distinguishing different types of FSs. Low PLR levels could be used to predict the risk of FS recurrence.
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Affiliation(s)
- Ling Tang
- Department of Clinical Laboratory, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, 214001, People's Republic of China
| | - Jie-Ru Chen
- Department of Paediatrics, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, 214001, People's Republic of China
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Ablation Techniques in Cancer Pain. Cancer Treat Res 2021; 182:157-174. [PMID: 34542882 DOI: 10.1007/978-3-030-81526-4_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Painful bone metastases are a frequently encountered problem in oncology practice. The skeletal system is the third most common site of metastatic disease and up to 85% of patients with breast, prostate, and lung cancer may develop bone metastases during the course of their disease.
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Starinets A, Tyrtyshnaia A, Kipryushina Y, Manzhulo I. Analgesic activity of synaptamide in a rat sciatic nerve chronic constriction injury model. Cells Tissues Organs 2021; 211:73-84. [PMID: 34510045 DOI: 10.1159/000519376] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/26/2021] [Indexed: 11/19/2022] Open
Affiliation(s)
- Anna Starinets
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Vladivostok, Russian Federation
| | - Anna Tyrtyshnaia
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Vladivostok, Russian Federation
| | - Yulia Kipryushina
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Vladivostok, Russian Federation
| | - Igor Manzhulo
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Vladivostok, Russian Federation
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Poulaki S, Rassouli O, Liapakis G, Gravanis A, Venihaki M. Analgesic and Anti-Inflammatory Effects of the Synthetic Neurosteroid Analogue BNN27 during CFA-Induced Hyperalgesia. Biomedicines 2021; 9:biomedicines9091185. [PMID: 34572370 PMCID: PMC8469064 DOI: 10.3390/biomedicines9091185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/01/2021] [Accepted: 09/07/2021] [Indexed: 01/02/2023] Open
Abstract
Dehydroepiandrosterone (DHEA), an adrenal and neurosteroid hormone with strong neuroprotective and immunomodulatory properties, and ligand for all high-affinity neurotrophin tyrosine kinase receptors (Trk), also exerts important effects on hyperalgesia. Its synthetic, 17-spiro-epoxy analogue, BNN27, cannot be converted to estrogen or androgen as DHEA; it is a specific agonist of TrkA, the receptor of pain regulator Nerve Growth Factor (NGF), and it conserves the immunomodulatory properties of DHEA. Our study aimed to evaluate the anti-nociceptive and anti-inflammatory properties of BNN27 during Complete Freund’s Adjuvant (CFA)-induced inflammatory hyperalgesia in mice. Hyperalgesia was evaluated using the Hargreaves test. Inflammatory markers such as cytokines, NGF and opioids were measured, additionally to corticosterone and the protein kinase B (AKT) signaling pathway. We showed for the first time that treatment with BNN27 reversed hyperalgesia produced by CFA. The effect of BNN27 involved the inhibition of NGF in the dorsal root ganglia (DRG) and the increased synthesis of opioid peptides and their receptors in the inflamed paw. We also found alterations in the cytokine levels as well as in the phosphorylation of AKT2. Our findings strongly support that BNN27 represents a lead molecule for the development of analgesic and anti-inflammatory compounds with potential therapeutic applications in inflammatory hyperalgesia.
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Affiliation(s)
- Smaragda Poulaki
- Department of Clinical Chemistry, Medical School, University of Crete, Voutes, 71110 Heraklion, Greece; (S.P.); (O.R.)
| | - Olga Rassouli
- Department of Clinical Chemistry, Medical School, University of Crete, Voutes, 71110 Heraklion, Greece; (S.P.); (O.R.)
| | - George Liapakis
- Department of Pharmacology, Medical School, University of Crete, Voutes, 71110 Heraklion, Greece; (G.L.); (A.G.)
| | - Achille Gravanis
- Department of Pharmacology, Medical School, University of Crete, Voutes, 71110 Heraklion, Greece; (G.L.); (A.G.)
- Institute of Molecular Biology & Biotechnology, Foundation of Research & Technology-Hellas, 71110 Heraklion, Greece
| | - Maria Venihaki
- Department of Clinical Chemistry, Medical School, University of Crete, Voutes, 71110 Heraklion, Greece; (S.P.); (O.R.)
- Correspondence: ; Tel.: +30-2810-394583
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Evolving role of minimally invasive techniques in the management of symptomatic bone metastases. Curr Opin Support Palliat Care 2021; 15:91-98. [PMID: 33905381 DOI: 10.1097/spc.0000000000000548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW Bone metastases are responsible for considerable morbidity, which can significantly limit a patient's quality of life. This article aims to review minimally invasive, image-guided locoregional treatments for symptomatic bone metastases as an adjunct to conventional treatment modalities. RECENT FINDINGS Conservative therapy and radiation therapy (RT) can be effective at addressing pain, however, they require time to achieve optimal efficacy and do not address the instability and progressive collapse of pathological fractures. Vertebral and pelvic augmentation with cement enhances structural stability and can prevent progressive collapse and deformity. Ablative therapies, including radiofrequency ablation (RFA), cryoablation, and photodynamic therapy (PDT), induce cellular destruction of tumor tissue. RFA and PDT can be combined with cement augmentation in a single sitting. SUMMARY Minimally invasive image-guided treatments can provide rapid pain relief, enhance mechanical stability, and improve quality of life. These treatments are associated with low complication rates and are suitable for frail patients. They can be used as companion procedures to conventional treatments, or function as an alternative for patients with radioresistant biologies or those with dose limitations from prior RT sessions.
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The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes. Mucosal Immunol 2021; 14:555-565. [PMID: 33542493 PMCID: PMC8075967 DOI: 10.1038/s41385-020-00368-1] [Citation(s) in RCA: 165] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 11/16/2020] [Accepted: 11/21/2020] [Indexed: 02/04/2023]
Abstract
The gastrointestinal tract is densely innervated by a complex network of neurons that coordinate critical physiological functions. Here, we summarize recent studies investigating the crosstalk between gut-innervating neurons, resident immune cells, and epithelial cells at homeostasis and during infection, food allergy, and inflammatory bowel disease. We introduce the neuroanatomy of the gastrointestinal tract, detailing gut-extrinsic neuron populations from the spinal cord and brain stem, and neurons of the intrinsic enteric nervous system. We highlight the roles these neurons play in regulating the functions of innate immune cells, adaptive immune cells, and intestinal epithelial cells. We discuss the consequences of such signaling for mucosal immunity. Finally, we discuss how the intestinal microbiota is integrated into the neuro-immune axis by tuning neuronal and immune interactions. Understanding the molecular events governing the intestinal neuro-immune signaling axes will enhance our knowledge of physiology and may provide novel therapeutic targets to treat inflammatory diseases.
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Pinto Fiamengui LMS, Furquim BD, De la Torre Canales G, Fonseca Carvalho Soares F, Poluha RL, Palanch Repeke CE, Bonjardim LR, Garlet GP, Rodrigues Conti PC. Role of inflammatory and pain genes polymorphisms in temporomandibular disorder and pressure pain sensitivity. Arch Oral Biol 2020; 118:104854. [PMID: 32763472 DOI: 10.1016/j.archoralbio.2020.104854] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/24/2020] [Accepted: 07/27/2020] [Indexed: 01/03/2023]
Abstract
OBJECTIVE The aim of this study was to assess the correlation of inflammatory and pain genes polymorphisms with the presence of temporomandibular disorder (TMD) patients and with pressure pain sensitivity. DESIGN Data was collected from 268 consecutive subjects at Bauru School of Dentistry. Subjects aged younger than 20 years, with dental and neuropathic pain, sinusitis, cognitive and neurologic disorder were excluded. Included subjects were evaluated using the Research Diagnostic Criteria for Temporomandibular disorders and divided into two groups: TMD cases and healthy controls. Groups were submitted to pressure pain threshold (PPT) test for the temporomandibular joint, anterior temporalis and masseter muscles and genotyped for Val158Met, IL6-174, IL-1β-3954 and TNFA-308. Student's t-test and Pearson chi-square test were used to comparisons between groups. A linear multiple regression was used to evaluate the influence of genetics variables on the PPT and a bivariate analysis was used to assesses the influence of genetics variables on pain sensitivity below the PPT cut off of the structures in TMD group. RESULTS TMD group showed significantly lower PPT values for all structures when compared with control group (p < 0.001). SNP IL6-174 predicted higher pain sensitivity in the temporomandibular joint (p < 0.005) and in anterior temporalis muscle (p < 0.044) and SNP Val158Met in the masseter muscle (p < 0.038); when TMD group was divided according to PPT cut-off values the SNP Val158Met influenced increase pain sensibility in the masseter muscle. CONCLUSION TNFA-308 was associated with TMD and SNP IL6-174 and SNP Val158Met influenced pain sensitivity of patients with TMD.
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Affiliation(s)
| | - Bruno D'Aurea Furquim
- Bauru Orofacial Pain Group, Department of Prosthodontics, Bauru School of Dentistry, University of São Paulo, Sao Paulo, Brazil
| | - Giancarlo De la Torre Canales
- Bauru Orofacial Pain Group, Department of Prosthodontics, Bauru School of Dentistry, University of São Paulo, Sao Paulo, Brazil.
| | - Flávia Fonseca Carvalho Soares
- Bauru Orofacial Pain Group, Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Sao Paulo, Brazil
| | - Rodrigo Lorenzi Poluha
- Bauru Orofacial Pain Group, Department of Prosthodontics, Bauru School of Dentistry, University of São Paulo, Sao Paulo, Brazil
| | | | - Leonardo Rigoldi Bonjardim
- Bauru Orofacial Pain Group, Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Sao Paulo, Brazil
| | | | - Paulo César Rodrigues Conti
- Bauru Orofacial Pain Group, Department of Prosthodontics, Bauru School of Dentistry, University of São Paulo, Sao Paulo, Brazil
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The role of Mean Platelet Volume/platelet count Ratio and Neutrophil to Lymphocyte Ratio on the risk of Febrile Seizure. Sci Rep 2018; 8:15123. [PMID: 30310107 PMCID: PMC6181908 DOI: 10.1038/s41598-018-33373-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 09/27/2018] [Indexed: 12/26/2022] Open
Abstract
Systemic inflammatory response has been implicated as a contributor to the onset of febrile seizures (FS). The four novel indices of the inflammatory response such as, neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV), platelet count (PLT) ratio and red blood cell distribution width (RDW) have been investigated in FS susceptibility and FS types (simple febrile seizure and complex febrile seizure). However, the potential role of these inflammatory markers and MPV/PLT ratio (MPR) in Chinese children with FS has yet to be fully determined. This study investigated the relevance of NLR, MPV, PLT, MPR and RDW in febrile children with and without seizures. 249 children with FS and 249 age matched controls were included in this study. NLR and MPR were calculated from complete blood cell counts prior to therapy. Differences in age, gender and these inflammatory markers between the FS group and the control group were evaluated using the chi-square test, t-test or logistic regression analysis. Receiver Operating Characteristic (ROC) curve was used to determine the optimal cut-off value of NLR and MPR for FS risk. Interactions between NLR and MPR on the additive scale were calculated by using the relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP), and the synergy index (S). It has been shown that the elevated NLR and MPR levels were associated with increased risk of FS. The optimal cut-off values of NLR and MPR for FS risk were 1.13 and 0.0335 with an area under the curve (AUC) of 0.768 and 0.689, respectively. Additionally, a significant synergistic interaction between NLR and MPR was found on an additive scale. The mean levels of MPV were lower and NLR levels were higher in complex febrile seizure (CFS) than simple febrile seizure (SFS), and the differences were statistically significant. ROC analysis showed that the optimal cut-off value for NLR was 2.549 with 65.9% sensitivity and 57.5% specificity. However, no statistically significant differences were found regarding average values of MPR and RDW between CFS and SFS. In conclusion, elevated NLR and MPR add evidence to the implication of white cells subsets in FS risk, and our results confirmed that NLR is an independent, albeit limited, predictor in differentiating between CFS and SFS. Moreover, NLR and MPR may have a synergistic effect that can influence the occurrence of FS.
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Stewart CL, Warner S, Ito K, Raoof M, Wu GX, Kessler J, Kim JY, Fong Y. Cytoreduction for colorectal metastases: liver, lung, peritoneum, lymph nodes, bone, brain. When does it palliate, prolong survival, and potentially cure? Curr Probl Surg 2018; 55:330-379. [PMID: 30526930 DOI: 10.1067/j.cpsurg.2018.08.004] [Citation(s) in RCA: 147] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 08/28/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Camille L Stewart
- Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA
| | - Susanne Warner
- Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA
| | - Kaori Ito
- Department of Surgery, Michigan State University, Lansing, MI
| | - Mustafa Raoof
- Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA
| | - Geena X Wu
- Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA
| | - Jonathan Kessler
- Department of Diagnostic Radiology, City of Hope National Medical Center, Duarte, CA
| | - Jae Y Kim
- Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA
| | - Yuman Fong
- Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA.
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A Functional riboSNitch in the 3' Untranslated Region of FKBP5 Alters MicroRNA-320a Binding Efficiency and Mediates Vulnerability to Chronic Post-Traumatic Pain. J Neurosci 2018; 38:8407-8420. [PMID: 30150364 DOI: 10.1523/jneurosci.3458-17.2018] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 07/11/2018] [Accepted: 07/13/2018] [Indexed: 01/30/2023] Open
Abstract
Previous studies have shown that common variants of the gene coding for FK506-binding protein 51 (FKBP5), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, FKBP5 rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional FKBP5 allele, rs3800373. This study assessed the association between rs3800373 and post-traumatic chronic pain in 1607 women and men from two ethnically diverse human cohorts. The molecular mechanism through which rs3800373 affects adverse outcomes was established via in silico, in vivo, and in vitro analyses. The rs3800373 minor allele predicted worse adverse outcomes after trauma exposure, such that individuals with the minor (risk) allele developed more severe post-traumatic chronic musculoskeletal pain. Among these individuals, peritraumatic circulating FKBP5 expression levels increased as cortisol and glucocorticoid receptor (NR3C1) mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, in vitro, and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress- and pain-associated microRNA, miR-320a, to FKBP5 via altering the FKBP5 mRNA 3'UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater FKBP5 translation, unchecked by miR-320a. Overall, these results identify an important gene-miRNA interaction influencing chronic pain risk in vulnerable individuals and suggest that exogenous methods to achieve targeted reduction in poststress FKBP5 mRNA expression may constitute useful therapeutic strategies.SIGNIFICANCE STATEMENT FKBP5 is a critical regulator of the stress response. Previous studies have shown that dysregulation of the expression of this gene plays a role in the pathogenesis of chronic pain development as well as a number of comorbid neuropsychiatric disorders. In the current study, we identified a functional allele (rs3800373) in the 3'UTR of FKBP5 that influences vulnerability to chronic post-traumatic pain in two ethnic cohorts. Using multiple complementary experimental approaches, we show that the FKBP5 rs3800373 minor allele alters the secondary structure of FKBP5 mRNA, decreasing the binding of a stress- and pain-associated microRNA, miR-320a. This results in relatively greater FKBP5 translation, unchecked by miR-320a, increasing glucocorticoid resistance and increasing vulnerability to post-traumatic pain.
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Arruri V, Komirishetty P, Areti A, Dungavath SKN, Kumar A. Nrf2 and NF-κB modulation by Plumbagin attenuates functional, behavioural and biochemical deficits in rat model of neuropathic pain. Pharmacol Rep 2017; 69:625-632. [PMID: 28505604 DOI: 10.1016/j.pharep.2017.02.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 12/24/2016] [Accepted: 02/03/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND Plumbagin is known to exhibit a broad range of biological activities including anti-cancer, antimicrobial and has been widely used traditionally. Nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) inhibitory and Nuclear factor (erythroid derived-2) like-2 (Nrf2) modulatory activities of Plumbagin have been reported already. In nerve injury model of neuropathy in rats, the role of NF-κB upregulation and declined antioxidant defence has been well recognized. So, we evaluated neuroprotective potential of Plumbagin in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in male Sprague-Dawley rats. METHODS Animals were tested for functional, behavioural and biochemical changes. Various markers associated with oxidative stress and inflammatory changes were assessed in the sciatic nerve and dorsal root ganglion (DRG) of the animals exposed to CCI mediated nerve injury. RESULTS CCI induced nerve injury led to long-lasting mechanical hyperalgesia, loss of hind limb function and abnormal pain sensation. Plumbagin treatment (10 and 20mg/kg, po) significantly and dose-dependently reversed mechanical hyperalgesia and other functional deficits. There was a marked increase in NF-κB and reduced Nrf2 levels in sciatic nerve and DRG following nerve injury. Plumbagin strengthened the antioxidant defence by improving Nrf2 levels and checked the neuroinflammation by decreasing NF-κB levels in sciatic nerve and DRG. CONCLUSIONS Together, these results suggested that Plumbagin alleviated CCI-induced neuropathic pain via antioxidant and anti-inflammatory mechanisms. Hence, the study suggests that Plumbagin may be useful for the management of trauma-induced neuropathic pain.
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Affiliation(s)
- Vijay Arruri
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India
| | - Prashanth Komirishetty
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India; Division of Neurology & Neuroscience and Mental Health Institute, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Aparna Areti
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India
| | - Siva Kumar Naik Dungavath
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India
| | - Ashutosh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India.
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Lynch JJ, Van Vleet TR, Mittelstadt SW, Blomme EAG. Potential functional and pathological side effects related to off-target pharmacological activity. J Pharmacol Toxicol Methods 2017; 87:108-126. [PMID: 28216264 DOI: 10.1016/j.vascn.2017.02.020] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 01/24/2017] [Accepted: 02/15/2017] [Indexed: 12/22/2022]
Abstract
Most pharmaceutical companies test their discovery-stage proprietary molecules in a battery of in vitro pharmacology assays to try to determine off-target interactions. During all phases of drug discovery and development, various questions arise regarding potential side effects associated with such off-target pharmacological activity. Here we present a scientific literature curation effort undertaken to determine and summarize the most likely functional and pathological outcomes associated with interactions at 70 receptors, enzymes, ion channels and transporters with established links to adverse effects. To that end, the scientific literature was reviewed using an on-line database, and the most commonly reported effects were summarized in tabular format. The resultant table should serve as a practical guide for research scientists and clinical investigators for the prediction and interpretation of adverse side effects associated with molecules interacting with components of this screening battery.
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Affiliation(s)
- James J Lynch
- AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
| | | | | | - Eric A G Blomme
- AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA
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20
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Abstract
Musculoskeletal pain (MSP) is a common sequela of traumatic stress exposure. While biological factors contributing to chronic MSP after motor vehicle collision (MVC) have traditionally focused on tissue injury, increasing evidence suggests that neuro/stress/immune processes mediated by stress system activation may play a more dominant role. In a previous study, we found that genetic variants in the hypothalamic-pituitary-adrenal (HPA) axis-related gene FKBP5 influence vulnerability to persistent MSP 6 weeks after MVC. In the present cohort study (n = 855), we evaluated whether genetic variants in several other important HPA axis-related genes, including the glucocorticoid receptor (NR3C1), corticotropin-releasing hormone receptor R1 (CRHR1), and corticotropin-releasing hormone-binding protein (CRHBP), influence risk of chronic MSP over time after MVC. Genetic polymorphism rs7718461 in the CRHBP gene showed significant association (P = 0.0012) with overall pain severity during the year after MVC in regression models controlling for multiple comparisons. Two additional CRHBP alleles in high linkage disequilibrium with rs7718461 also showed trend-level significance. In secondary analyses, a significant interaction between this CRHBP locus (minor allele frequency = 0.33) and time was observed (P = 0.015), with increasing effect observed over time following trauma. A significant CRHBP × FKBP5 interaction was also observed, with substantially increased MSP after MVC in those with a risk allele in both genes compared with either gene alone. The results of this study indicate that genetic variants in 2 different HPA axis genes predict chronic MSP severity following MVC and support the hypothesis that the HPA axis is involved in chronic post-MVC MSP pathogenesis.
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Sun S, Chen D, Lin F, Chen M, Yu H, Hou L, Li C. Role of interleukin-4, the chemokine CCL3 and its receptor CCR5 in neuropathic pain. Mol Immunol 2016; 77:184-192. [PMID: 27522478 DOI: 10.1016/j.molimm.2016.08.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 08/04/2016] [Accepted: 08/04/2016] [Indexed: 02/08/2023]
Abstract
Cytokines and chemokines are involved in chronic pain syndromes, and their expression is altered in injury-induced neuronal pain pathways. However, the exact cytokines/chemokines involved and their mechanism of action remain to be determined. In this study, we investigated the role of interleukin-4 and the chemokine/chemokine receptor pair CCL3/CCR5 in a mouse model of chronic constriction injury (CCI)-induced neuropathic pain. Neuropathic pain was induced by surgical ligation of the sciatic nerve and assessed by measuring thermal hyperalgesia and mechanical allodynia using a plantar test and a dynamic plantar esthesiometer. The underlying mechanisms were investigated by real-time quantitative reverse transcription polymerase chain reaction, western blotting, immunohistochemistry, ELISA, and histopathology. CCI-induced neuropathic pain was associated with CCL3 and CCR5 upregulation and microglial activation. Intrathecal injection of the anti-inflammatory cytokine interleukin-4 or CCL3-neutralizing antibody alleviated CCI-induced inflammation, suppressing the CCI-induced upregulation of tumor necrosis factor-α and interleukin-1β in the serum and spinal cord, restoring the CCI-induced upregulation of CCL3 and CCR5, and suppressing the CCI-induced activation of p38 mitogen-activated protein kinase. Knockout of CCR5 also suppressed CCI-induced neuropathic pain. Since the upregulation of chemokines and cytokines is directly or indirectly involved in chronic pain after nerve injury, these molecules are potential therapeutic targets in the treatment of neuropathic pain.
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Affiliation(s)
- Shiyu Sun
- Department of Anaesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Dan Chen
- Department of Anaesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Fuqing Lin
- Department of Anaesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| | - Minghui Chen
- Department of Anaesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Hongli Yu
- Department of Anaesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Lengchen Hou
- Department of Anaesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Cheng Li
- Department of Anaesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
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Multiplex Immunoassay of Plasma Cytokine Levels in Men with Alcoholism and the Relationship to Psychiatric Assessments. Int J Mol Sci 2016; 17:472. [PMID: 27043532 PMCID: PMC4848928 DOI: 10.3390/ijms17040472] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 03/22/2016] [Accepted: 03/24/2016] [Indexed: 12/26/2022] Open
Abstract
Chronic alcohol use alters adaptive immunity and cytokine activity influencing immunological and hormone responses, inflammation, and wound healing. Brain cytokine disturbances may impact neurological function, mood, cognition and traits related to alcoholism including impulsiveness. We examined the relationship between plasma cytokine levels and self-rated psychiatric symptoms in 40 adult males (mean age 51 ± 6 years; range 33–58 years) with current alcohol dependence and 30 control males (mean age 48 ± 6 years; range 40–58 years) with no history of alcoholism using multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Log-transformed cytokine levels were analyzed for their relationship with the Symptom Checklist-90R (SCL-90R), Barratt Impulsivity Scales (BIS) and Alcoholism Severity Scale (ASS). Inflammatory cytokines (interferon γ-induced protein-10 (IP-10); monocyte chemoattractant protein-1 (MCP1); regulated on activation, normal T cell expressed and secreted (RANTES)) were significantly elevated in alcoholism compared to controls while bone marrow-derived hematopoietic cytokines and chemokines (granulocyte-colony stimulating factor (GCSF); soluble CD40 ligand (sCD40L); growth-related oncogene (GRO)) were significantly reduced. GRO and RANTES levels were positively correlated with BIS scales; and macrophage-derived chemokine (MDC) levels were positively correlated with SCL-90R scale scores (p < 0.05). Elevated inflammatory mediators in alcoholism may influence brain function leading to increased impulsiveness and/or phobia. The novel association between RANTES and GRO and impulsivity phenotype in alcoholism should be further investigated in alcoholism and psychiatric conditions with core impulsivity and anxiety phenotypes lending support for therapeutic intervention.
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The Anti-Inflammatory Actions of Auricular Point Acupressure for Chronic Low Back Pain. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:103570. [PMID: 26170869 PMCID: PMC4480805 DOI: 10.1155/2015/103570] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 03/01/2015] [Accepted: 03/02/2015] [Indexed: 12/12/2022]
Abstract
Background. Auricular point acupressure (APA) is a promising treatment for pain management. Few studies have investigated the physiological mechanisms of APA analgesics. Method. In this pilot randomized clinical trial (RCT), a 4-week APA treatment was used to manage chronic low back pain (CLBP). Sixty-one participants were randomized into a real APA group (n = 32) or a sham APA group (n = 29). Blood samples, pain intensity, and physical function were collected at baseline and after 4 weeks of treatment. Results. Subjects in the real APA group reported a 56% reduction of pain intensity and a 26% improvement in physical function. Serum blood samples showed (1) a decrease in IL-1β, IL-2, IL-6, and calcitonin gene-related peptide [CGRP] and (2) an increase in IL-4. In contrast, subjects in the sham APA group (1) reported a 9% reduction in pain and a 2% improvement in physical function and (2) exhibited minimal changes of inflammatory cytokines and neuropeptides. Statistically significant differences in IL-4 and CGRP expression between the real and sham APA groups were verified. Conclusion. These findings suggest that APA treatment affects pain intensity through modulation of the immune system, as reflected by APA-induced changes in serum inflammatory cytokine and neuropeptide levels.
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Shattuck EC, Muehlenbein MP. Human sickness behavior: Ultimate and proximate explanations. AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 2015; 157:1-18. [DOI: 10.1002/ajpa.22698] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Revised: 12/27/2014] [Accepted: 12/28/2014] [Indexed: 12/22/2022]
Affiliation(s)
- Eric C. Shattuck
- Evolutionary Physiology and Ecology Laboratory; Department of Anthropology; Indiana University; Bloomington IN
| | - Michael P. Muehlenbein
- Evolutionary Physiology and Ecology Laboratory; Department of Anthropology; Indiana University; Bloomington IN
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26
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Mahyar A, Ayazi P, Orangpour R, Daneshi-Kohan MM, Sarokhani MR, Javadi A, Habibi M, Talebi-Bakhshayesh M. Serum interleukin-1beta and tumor necrosis factor-alpha in febrile seizures: is there a link? KOREAN JOURNAL OF PEDIATRICS 2014; 57:440-4. [PMID: 25379044 PMCID: PMC4219946 DOI: 10.3345/kjp.2014.57.10.440] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2013] [Revised: 10/07/2013] [Accepted: 01/22/2014] [Indexed: 12/12/2022]
Abstract
Purpose Febrile seizures are induced by fever and are the most common type of seizures in children. Although numerous studies have been performed on febrile seizures, their pathophysiology remains unclear. Recent studies have shown that cytokines may play a role in the pathogenesis of febrile seizures. The present study was conducted to identify potential links between serum interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and febrile seizures. Methods Ninety-two patients with simple or complex febrile seizures (46 patients per seizure type), and 46 controls with comparable age, sex, and severity of temperature were enrolled. Results The median concentrations of serum IL-1β in the simple, complex febrile seizure, and control groups were 0.05, 0.1, and 0.67 pg/mL, respectively (P=0.001). Moreover, the median concentrations of TNF-α in the simple, complex febrile seizure, and control groups were 2.5, 1, and 61.5 pg/mL, respectively (P=0.001). Furthermore, there were significant differences between the case groups in serum IL-1β and TNF-α levels (P<0.05). Conclusion Unlike previous studies, our study does not support the hypothesis that increased IL-1β and TNF-α production is involved in the pathogenesis of febrile seizures.
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Affiliation(s)
- Abolfazl Mahyar
- Department of Pediatrics, Qazvin Children Hospital, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Parviz Ayazi
- Department of Pediatrics, Qazvin Children Hospital, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Reza Orangpour
- Department of Pediatrics, Qazvin Children Hospital, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | - Mohammad Reza Sarokhani
- Department of Pediatrics, Qazvin Children Hospital, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amir Javadi
- Department of Pediatrics, Qazvin Children Hospital, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Morteza Habibi
- Department of Pediatrics, Qazvin Children Hospital, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mousa Talebi-Bakhshayesh
- Department of Pediatrics, Qazvin Children Hospital, Qazvin University of Medical Sciences, Qazvin, Iran
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Rodrigues R, Debom G, Soares F, Machado C, Pureza J, Peres W, de Lima Garcias G, Duarte MF, Schetinger MRC, Stefanello F, Braganhol E, Spanevello R. Alterations of ectonucleotidases and acetylcholinesterase activities in lymphocytes of Down syndrome subjects: relation with inflammatory parameters. Clin Chim Acta 2014; 433:105-10. [PMID: 24631131 DOI: 10.1016/j.cca.2014.03.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Revised: 02/22/2014] [Accepted: 03/03/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND Subjects with Down syndrome (DS) have an increased susceptibility to infections and autoimmune disorders. ATP, adenosine, and acetylcholine contribute to the immune response regulation, and NTPDase, adenosine deaminase (ADA) and acetylcholinesterase (AChE) are important enzymes in the control of the extracellular levels of these molecules. We evaluated the activities of these enzymes and the cytokine levels in samples of DS individuals. METHODS The population consisted of 23 subjects with DS and 23 healthy subjects. Twelve milliliters of blood was obtained from each subject and used for lymphocyte and serum preparation. Lymphocytes were separated on Ficoll density gradients. After isolation, NTPDase and AChE activities were determined. RESULTS The NTPDase activity using ADP as substrate was increased in lymphocytes of DS patients compared to control (P<0.05); however, no alterations were observed in the ATP hydrolysis. An increase was observed in the AChE activity in lymphocytes and in ADA activity in serum of DS patients when compared to healthy subjects (P<0.05). In DS subjects, an increase in the levels of IL-1β, IL-6, TNF-α and IFN-γ and a decrease in the IL-10 levels were also observed (P<0.05). CONCLUSIONS Alterations in the NTPDase, ADA and AChE activities as well changes in the cytokine levels may contribute to immunological alterations observed in DS.
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Affiliation(s)
- Rodrigo Rodrigues
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - Gabriela Debom
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - Fabiano Soares
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - Caroline Machado
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - Jéssica Pureza
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - William Peres
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | | | - Marta Frescura Duarte
- Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Av. Roraima, 97105-900 Santa Maria, RS, Brazil
| | - Maria Rosa Chitolina Schetinger
- Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Av. Roraima, 97105-900 Santa Maria, RS, Brazil
| | - Francieli Stefanello
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - Elizandra Braganhol
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - Roselia Spanevello
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil.
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Liou JT, Lee CM, Day YJ. The immune aspect in neuropathic pain: role of chemokines. ACTA ACUST UNITED AC 2013; 51:127-32. [PMID: 24148742 DOI: 10.1016/j.aat.2013.08.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 08/26/2013] [Accepted: 08/29/2013] [Indexed: 12/23/2022]
Abstract
Neuropathic pain is a pathological symptom experienced worldwide by patients suffering with nervous system dysfunction caused by various diseases. Treatment of neuropathic pain is always accompanied by a poor response and undesired adverse effects. Therefore, developing a novel "pain-kill" drug design strategy is critical in this field. Recent evidence demonstrates that neuroinflammation and immune response contributes to the development of neuropathic pain. Nerve damage can initiate inflammatory and immune responses, as evidenced by the upregulation of cytokines and chemokines. In this paper, we demonstrated that different chemokines and chemokine receptors (e.g., CX3CL1/CX3CR1, CCL2/CCR2, CCL3/CCR1, CCL4/CCR5 and CCL5/CCR5) serve as mediators for neuron-glia communication subsequently modulate nociceptive signal transmission. By extensively understanding the role of chemokines in neurons and glial cells in nociceptive signal transmission, a novel strategy for a target-specific drug design could be developed.
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Affiliation(s)
- Jiin-Tarng Liou
- Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan; Molecular Immunogenetics Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan
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29
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VanElzakker MB. Chronic fatigue syndrome from vagus nerve infection: A psychoneuroimmunological hypothesis. Med Hypotheses 2013; 81:414-23. [DOI: 10.1016/j.mehy.2013.05.034] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Revised: 05/15/2013] [Accepted: 05/23/2013] [Indexed: 12/20/2022]
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Zielinski MR, Dunbrasky DL, Taishi P, Souza G, Krueger JM. Vagotomy attenuates brain cytokines and sleep induced by peripherally administered tumor necrosis factor-α and lipopolysaccharide in mice. Sleep 2013; 36:1227-38, 1238A. [PMID: 23904683 DOI: 10.5665/sleep.2892] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
STUDY OBJECTIVE Systemic tumor necrosis factor-α (TNF-α) is linked to sleep and sleep altering pathologies in humans. Evidence from animals indicates that systemic and brain TNF-α have a role in regulating sleep. In animals, TNF-α or lipopolysaccharide (LPS) enhance brain pro-inflammatory cytokine expression and sleep after central or peripheral administration. Vagotomy blocks enhanced sleep induced by systemic TNF-α and LPS in rats, suggesting that vagal afferent stimulation by TNF-α enhances pro-inflammatory cytokines in sleep-related brain areas. However, the effects of systemic TNF-α on brain cytokine expression and mouse sleep remain unknown. DESIGN We investigated the role of vagal afferents on brain cytokines and sleep after systemically applied TNF-α or LPS in mice. MEASUREMENTS AND RESULTS Spontaneous sleep was similar in vagotomized and sham-operated controls. Vagotomy attenuated TNF-α- and LPS-enhanced non-rapid eye movement sleep (NREMS); these effects were more evident after lower doses of these substances. Vagotomy did not affect rapid eye movement sleep responses to these substances. NREMS electroencephalogram delta power (0.5-4 Hz range) was suppressed after peripheral TNF-α or LPS injections, although vagotomy did not affect these responses. Compared to sham-operated controls, vagotomy did not affect liver cytokines. However, vagotomy attenuated interleukin-1 beta (IL-1β) and TNF-α mRNA brain levels after TNF-α, but not after LPS, compared to the sham-operated controls. CONCLUSIONS We conclude that vagal afferents mediate peripheral TNF-α-induced brain TNF-α and IL-1β mRNA expressions to affect sleep. We also conclude that vagal afferents alter sleep induced by peripheral pro-inflammatory stimuli in mice similar to those occurring in other species.
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Affiliation(s)
- Mark R Zielinski
- Sleep and Performance Research Center, Washington State University, Spokane, WA 99210-1495, USA
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31
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O' Mahony SM, Clarke G, McKernan DP, Bravo JA, Dinan TG, Cryan JF. Differential visceral nociceptive, behavioural and neurochemical responses to an immune challenge in the stress-sensitive Wistar Kyoto rat strain. Behav Brain Res 2013; 253:310-7. [PMID: 23872358 DOI: 10.1016/j.bbr.2013.07.023] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Revised: 07/11/2013] [Accepted: 07/14/2013] [Indexed: 01/08/2023]
Abstract
A highly regulated crosstalk exists between the immune and neuroendocrine systems with the altered immune responses in stress-related disorders being a valid example of this interaction. The Wister Kyoto (WKY) rat is an animal model with a genetic predisposition towards an exaggerated stress response and is used to study disorders such as depression and irritable bowel syndrome (IBS), where stress plays a substantial role. The impact of a lipopolysaccride (LPS) immune challenge has not yet been investigated in this animal model to date. Hence our aim was to assess if the stress susceptible genetic background of the WKY rat was associated with a differential response to an acute immune challenge. Central and peripheral parameters previously shown to be altered by LPS administration were assessed. Under baseline conditions, WKY rats displayed visceral hypersensitivity compared to Sprague Dawley (SD) control rats. However, only SD rats showed an increase in visceral sensitivity following endotoxin administration. The peripheral immune response to the LPS was similar in both strains whilst the central neurochemistry was blunted in the WKY rats. Sickness behaviour was also abrogated in the WKY rats. Taken together, these data indicate that the genetic background of the WKY rat mitigates the response to infection centrally, but not peripherally. This implies that heightened stress-susceptibility in vulnerable populations may compromise the coordinated CNS response to peripheral immune activation.
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Quinson N, Vitton V, Bouvier M, Grimaud JC, Abysique A. Effects of tumor necrosis factor α on leptin-sensitive intestinal vagal mechanoreceptors in the cat. Can J Physiol Pharmacol 2013; 91:941-50. [PMID: 24117262 DOI: 10.1139/cjpp-2013-0025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The involvement of tumour necrosis factor α (TNF-α) in inflammatory bowel disease (IBD) has been established, and anti-TNF-α has been suggested as a therapeutic approach for the treatment of these pathologies. We studied the effects of TNF-α on leptin-sensitive intestinal vagal units to determine whether TNF-α exerts its effects through the intestinal vagal mechanoreceptors and to investigate its interactions with substances regulating food intake. The activity of intestinal vagal mechanoreceptors was recorded via microelectrodes implanted into the nodose ganglion in anesthetized cats. TNF-α (1 μg, i.a.) increased the discharge frequency of leptin-activated units (type 1 units; P < 0.05) and had no effect on the discharge frequency of leptin-inhibited units (type 2 units). When TNF-α was administered 20 min after sulfated cholecystokinin-8 (CCK), its excitatory effects on type 1 units were significantly enhanced (P < 0.0001) and type 2 units were significantly (P < 0.05) activated. Pre-treatment with Il-1ra (250 μg, i.a.) blocked the excitatory effects of TNF-α on type 1 units whereas the excitatory effects of TNF-α administration after CCK treatment on type 2 units were not modified. The activation of leptin-sensitive units by TNF-α may explain, at least in part, the weight loss observed in IBD.
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Affiliation(s)
- Nathalie Quinson
- a Aix Marseille Université, Physiologie et Physiopathologie du Système Nerveux Somatomoteur et Neurovégétatif (PPSN, EA4674), Avenue Escadrille Normandie Niemen, 13397 Marseille Cedex 20, France
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Duncan M, Galic MA, Wang A, Chambers AP, McCafferty DM, McKay DM, Sharkey KA, Pittman QJ. Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation. Am J Physiol Regul Integr Comp Physiol 2013; 305:R224-31. [PMID: 23739343 DOI: 10.1152/ajpregu.00104.2013] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Sickness behaviors are host defense adaptations that arise from integrated autonomic outputs in response to activation of the innate immune system. These behaviors include fever, anorexia, and hyperalgesia intended to promote survival of the host when encountering pathogens. Cannabinoid (CB) receptor activation can induce hypothermia and attenuate LPS-evoked fever. The aim of the present study was to examine the role of CB1 receptors in the LPS-evoked febrile response. CB1 receptor-deficient (CB1(-/-)) mice did not display LPS-evoked fever; likewise, pharmacological blockade of CB1 receptors in wild-type mice blocked LPS-evoked fever. This unresponsiveness is not limited to thermogenesis, as the animals were not hyperalgesic after LPS administration. A Toll-like receptor (TLR)3 agonist and viral mimetic polyinosinic:polycytidylic acid evoked a robust fever in CB1(-/-) mice, suggesting TLR3-mediated responses are functional. LPS-evoked c-Fos activation in areas of the brain associated with the febrile response was evident in wild-type mice but not in CB1(-/-) mice. Liver and spleen TLR4 mRNA were significantly lower in CB1(-/-) mice compared with wild-type mice, and peritoneal macrophages from CB1(-/-) mice did not release proinflammatory cytokines in response to LPS. These data indicate that CB1 receptors play a critical role in LPS-induced febrile responses through inhibiting TLR4-mediated cytokine production.
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Affiliation(s)
- Marnie Duncan
- Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
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Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-α and IL-1β is mediated by glial cells. J Neurosci 2013; 33:6540-51. [PMID: 23575851 DOI: 10.1523/jneurosci.5087-12.2013] [Citation(s) in RCA: 173] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Long-term potentiation (LTP) of synaptic strength in nociceptive pathways is a cellular model of hyperalgesia. The emerging literature suggests a role for cytokines released by spinal glial cells for both LTP and hyperalgesia. However, the underlying mechanisms are still not fully understood. In rat lumbar spinal cord slices, we now demonstrate that conditioning high-frequency stimulation of primary afferents activated spinal microglia within <30 min and spinal astrocytes within ~2 s. Activation of spinal glia was indispensible for LTP induction at C-fiber synapses with spinal lamina I neurons. The cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), which are both released by activated glial cells, were individually sufficient and necessary for LTP induction via redundant pathways. They differentially amplified 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propanoic acid receptor-mediated and N-methyl-D-aspartic acid receptor-mediated synaptic currents in lamina I neurons. Unexpectedly, the synaptic effects by IL-1β and TNF-α were not mediated directly via activation of neuronal cytokine receptors, but rather, indirectly via IL-1 receptors and TNF receptors being expressed on glial cells in superficial spinal dorsal horn. Bath application of IL-1β or TNF-α led to the release profiles of pro-inflammatory and anti-inflammatory cytokines, chemokines, and growth factors, which overlapped only partially. Heat hyperalgesia induced by spinal application of either IL-1β or TNF-α in naive animals also required activation of spinal glial cells. These results reveal a novel, decisive role of spinal glial cells for the synaptic effects of IL-1β and TNF-α and for some forms of hyperalgesia.
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Bortsov AV, Smith JE, Diatchenko L, Soward AC, Ulirsch JC, Rossi C, Swor RA, Hauda WE, Peak DA, Jones JS, Holbrook D, Rathlev NK, Foley KA, Lee DC, Collette R, Domeier RM, Hendry PL, McLean SA. Polymorphisms in the glucocorticoid receptor co-chaperone FKBP5 predict persistent musculoskeletal pain after traumatic stress exposure. Pain 2013; 154:1419-26. [PMID: 23707272 DOI: 10.1016/j.pain.2013.04.037] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Revised: 04/18/2013] [Accepted: 04/22/2013] [Indexed: 11/19/2022]
Abstract
Individual vulnerability factors influencing the function of the hypothalamic-pituitary-adrenal axis may contribute to the risk of the development of persistent musculoskeletal pain after traumatic stress exposure. The objective of the study was to evaluate the association between polymorphisms in the gene encoding FK506 binding protein 51, FKBP5, a glucocorticoid receptor co-chaperone, and musculoskeletal pain severity 6 weeks after 2 common trauma exposures. The study included data from 2 prospective emergency department-based cohorts: a discovery cohort (n=949) of European Americans experiencing motor vehicle collision and a replication cohort of adult European American women experiencing sexual assault (n=53). DNA was collected from trauma survivors at the time of initial assessment. Overall pain and neck pain 6 weeks after trauma exposure were assessed using a 0-10 numeric rating scale. After adjustment for multiple comparisons, 6 FKBP5 polymorphisms showed significant association (minimum P<0.0001) with both overall and neck pain in the discovery cohort. The association of rs3800373, rs9380526, rs9394314, rs2817032, and rs2817040 with neck pain and/or overall pain 6 weeks after trauma was replicated in the sexual assault cohort, showing the same direction of the effect in each case. The results of this study indicate that genetic variants in FKBP5 influence the severity of musculoskeletal pain symptoms experienced during the weeks after motor vehicle collision and sexual assault. These results suggest that glucocorticoid pathways influence the development of persistent posttraumatic pain, and that such pathways may be a target of pharmacologic interventions aimed at improving recovery after trauma.
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Affiliation(s)
- Andrey V Bortsov
- TRYUMPH Research Program, University of North Carolina, Chapel Hill, NC, USA
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Chronic-pain-associated astrocytic reaction in the spinal cord dorsal horn of human immunodeficiency virus-infected patients. J Neurosci 2012; 32:10833-40. [PMID: 22875918 DOI: 10.1523/jneurosci.5628-11.2012] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Studies with animal models have suggested that reaction of glia, including microglia and astrocytes, critically contributes to the development and maintenance of chronic pain. However, the involvement of glial reaction in human chronic pain is unclear. We performed analyses to compare the glial reaction profiles in the spinal dorsal horn (SDH) from three cohorts of sex- and age-matched human postmortem tissues: (1) HIV-negative patients, (2) HIV-positive patients without chronic pain, and (3) HIV patients with chronic pain. Our results indicate that the expression levels of CD11b and Iba1, commonly used for labeling microglial cells, did not differ in the three patient groups. However, GFAP and S100β, often used for labeling astrocytes, were specifically upregulated in the SDH of the "pain-positive" HIV patients but not in the "pain-negative" HIV patients. In addition, proinflammatory cytokines, TNFα and IL-1β, were specifically increased in the SDH of pain-positive HIV patients. Furthermore, proteins in the MAPK signaling pathway, including pERK, pCREB and c-Fos, were also upregulated in the SDH of pain-positive HIV patients. Our findings suggest that reaction of astrocytes in the SDH may play a role during the maintenance phase of HIV-associated chronic pain.
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Licciardone JC, Kearns CM, Hodge LM, Bergamini MV. Associations of Cytokine Concentrations With Key Osteopathic Lesions and Clinical Outcomes in Patients With Nonspecific Chronic Low Back Pain: Results From the OSTEOPATHIC Trial. J Osteopath Med 2012; 112:596-605. [DOI: 10.7556/jaoa.2012.112.9.596] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Abstract
Context: Little is known about the role that cytokines play in osteopathic manual treatment (OMT) of patients with chronic low back pain (LBP).
Objective: To measure the baseline concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α in patients with chronic LBP; the correlations of these cytokine concentrations with clinical measures, including the number of key osteopathic lesions; the changes in cytokine concentrations with OMT; and the association of such changes with clinical outcomes.
Design: Substudy nested within a randomized controlled trial of OMT for nonspecific chronic LBP.
Setting: University-based study in Dallas-Fort Worth, Texas.
Patients: Seventy adult research patients with nonspecific chronic LBP.
Main Outcome Measures: A 10-cm visual analog scale, the Roland-Morris Disability Questionnaire, and the Medical Outcomes Study Short Form-36 Health Survey were used to measure LBP severity, back-specific functioning, and general health, respectively.
Results:At baseline, IL-1β (ρ=0.33; P=.005) and IL-6 (ρ=0.32; P=.006) were each correlated with the number of key osteopathic lesions; however, only IL-6 was correlated with LBP severity (ρ=0.28; P=.02). There was a significantly greater reduction of TNF-α concentration after 12 weeks in patients who received OMT compared with patients who received sham OMT (Mann-Whitney U=251.5; P=.03). Significant associations were found between OMT and a reduced TNF-α concentration response at week 12 among patients who achieved moderate (response ratio, 2.13; 95% confidence interval [CI], 1.11-4.06; P=.006) and substantial (response ratio, 2.13; 95% CI, 1.07-4.25; P=.01) LBP improvements, and improvement in back-specific functioning (response ratio, 1.68; 95% CI, 1.04-2.71; P=.03).
Conclusions: This study found associations between IL-1β and IL-6 concentrations and the number of key osteopathic lesions and between IL-6 and LBP severity at baseline. However, only TNF-α concentration changed significantly after 12 weeks in response to OMT. These discordant findings indicate that additional research is needed to elucidate the underlying mechanisms of action of OMT in patients with nonspecific chronic LBP.
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38
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Krenk L, Jennum P, Kehlet H. Sleep disturbances after fast-track hip and knee arthroplasty. Br J Anaesth 2012; 109:769-75. [PMID: 22831887 DOI: 10.1093/bja/aes252] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Major surgery is followed by pronounced sleep disturbances after traditional perioperative care potentially leading to prolonged recovery. The aim was to evaluate the rapid eye movement (REM) sleep duration and sleep architecture before and after fast-track hip and knee replacement with length of stay (LOS) <3 days. The primary endpoint was REM sleep duration on the first postoperative night compared with before operation. METHODS Ten subjects (≥60 yr) receiving spinal anaesthesia and multimodal opioid-sparing postoperative analgesia for total hip or knee arthroplasty were included. Ambulatory polysomnography was performed one night before operation at home, continuously during hospitalization, and on the fourth postoperative night at home. Sleep staging was performed according to the American Academy of Sleep Medicine manual. Opioid use, pain, and inflammatory response (C-reactive protein) were also evaluated. RESULTS The mean LOS was 1.5 (1-2) days. The mean REM sleep time decreased from a mean of 18.2 (9.5-23.5)% of total sleep time to 1.2 (0-5.8)% on the first postoperative night (P=0.002); awake time increased from 19.1 (3.7-44.4)% to 44.3 (12.2-70.6)% (P=0.009); and sleep architecture on the first postoperative night was more disturbed than before operation. Sleep architecture normalized on the fourth postoperative night. There was no association between opioid use, pain scores, and inflammatory response with a disturbed sleep pattern. CONCLUSIONS Despite ultra-short LOS and provision of spinal anaesthesia with multimodal opioid-sparing analgesia, REM sleep was almost eliminated on the first postoperative night after fast-track orthopaedic surgery but returned to pre-admission levels when at home on the fourth postoperative night.
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Affiliation(s)
- L Krenk
- Section of Surgical Pathophysiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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39
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Rausch SM, Gonzalez BD, Clark MM, Patten C, Felten S, Liu H, Li Y, Sloan J, Yang P. SNPs in PTGS2 and LTA predict pain and quality of life in long term lung cancer survivors. Lung Cancer 2012; 77:217-23. [PMID: 22464751 PMCID: PMC4314090 DOI: 10.1016/j.lungcan.2012.02.017] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Revised: 01/18/2012] [Accepted: 02/22/2012] [Indexed: 11/24/2022]
Abstract
PURPOSE Lung cancer survivors report the lowest quality of life relative to other cancer survivors. Pain is one of the most devastating, persistent, and incapacitating symptoms for lung cancer survivors. Prevalence rates vary with 80-100% of survivors experiencing cancer pain and healthcare costs are five times higher in cancer survivors with uncontrolled pain. Cancer pain often has a considerable impact on quality of life among cancer patients and cancer survivors. Therefore, early identification, and treatment is important. Although recent studies have suggested a relationship between single nucleotide polymorphisms (SNPs) in several cytokine and inflammation genes with cancer prognosis, associations with cancer pain are not clear. Therefore, the primary aim of this study was to identify SNPs related to pain in lung cancer survivors. PATIENTS AND METHODS Participants were enrolled in the Mayo Clinic Lung Cancer Cohort upon diagnosis of their lung cancer. 1149 Caucasian lung cancer survivors (440 surviving <3 years; 354 surviving 3-5 years; and 355 surviving >5 years) completed study questionnaires and had blood DNA samples available. Ten SNPS from PTGS2 and LTA genes were selected based on the serum-based studies in the literature. Outcomes included pain, and quality of life as measured by the SF-8. RESULTS Of the 10 SNPs evaluated in LTA and PTGS2 genes, 3 were associated with pain severity (rs5277; rs1799964), social function (rs5277) and mental health (rs5275). These results suggested both specificity and consistency of these inflammatory gene SNPs in predicting pain severity in lung cancer survivors. CONCLUSION These results provide support for genetic predisposition to pain severity and may aid in identification of lung cancer survivors at high risk for morbidity and poor QOL.
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Affiliation(s)
- Sarah M. Rausch
- Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612
| | - Brian D. Gonzalez
- Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612
| | | | | | - Sara Felten
- Mayo Clinic, 200 First St SW, Rochester, MN 55905
| | - Heshan Liu
- Mayo Clinic, 200 First St SW, Rochester, MN 55905
| | - Yafei Li
- Mayo Clinic, 200 First St SW, Rochester, MN 55905
| | - Jeff Sloan
- Mayo Clinic, 200 First St SW, Rochester, MN 55905
| | - Ping Yang
- Mayo Clinic, 200 First St SW, Rochester, MN 55905
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Yoon SY, Patel D, Dougherty PM. Minocycline blocks lipopolysaccharide induced hyperalgesia by suppression of microglia but not astrocytes. Neuroscience 2012; 221:214-24. [PMID: 22742905 DOI: 10.1016/j.neuroscience.2012.06.024] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Revised: 06/08/2012] [Accepted: 06/09/2012] [Indexed: 12/26/2022]
Abstract
Systemic injection of lipopolysaccharide (LPS) induces a robust immune response as well as thermal and mechanical hyperalgesia. Spinal and peripheral glial cells have been implicated as important mediators in this hyperalgesia but the specific contributions of microglia versus astrocytes are not entirely clear. To better define these mechanisms, this study examined the febrile response, nociceptive sensitivity, glial cell reactivity and cytokine production in the dorsal root ganglion (DRG) and spinal cord in rats following systemic treatment with LPS and the effects of minocycline in countering these responses. Intraperitoneal LPS injection resulted in an increase in core body temperature and produced hyperalgesia to heat and mechanical stimuli. Western blot studies revealed increased expression of microgial cell, macrophage and satellite cell markers in DRG and microglial and astrocyte markers in spinal cord following LPS treatment. Real-time RT-PCR indicated that LPS treatment increased cytokine mRNA expression levels in both the DRG and the spinal cord. Minocycline suppressed all LPS-induced behavioral effects but not the febrile response. Moreover, minocycline prevented LPS-induced microglia/macrophage activation and cytokine responses in spinal cord and DRG, but did not affect the activation of astrocytes/satellite cells. These data demonstrate that LPS-induced changes in nociceptive sensitivity are likely mediated by activation of microglial cells and/or macrophages in the spinal cord and DRG.
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Affiliation(s)
- S-Y Yoon
- Laboratory of Molecular Signal Transduction, Center for Neural Science, Korea Institute of Science and Technology, Seoul, South Korea
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Turabi A, Plunkett AR. The application of genomic and molecular data in the treatment of chronic cancer pain. J Surg Oncol 2012; 105:494-501. [DOI: 10.1002/jso.21707] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Macrophage-mediated dorsal root ganglion damage precedes altered nerve conduction in SIV-infected macaques. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:2337-45. [PMID: 21924225 DOI: 10.1016/j.ajpath.2011.07.047] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Revised: 06/21/2011] [Accepted: 07/11/2011] [Indexed: 12/26/2022]
Abstract
Peripheral neuropathy is the most common neurological complication of HIV-1 infection, affecting over one-third of infected individuals, including those treated with antiretroviral therapy. To study the pathogenesis of HIV-induced peripheral nervous system disease, we established a model in which SIV-infected macaques developed changes closely resembling alterations reported in components of the sensory pathway in HIV-infected individuals. Significant declines in epidermal nerve fiber density developed in SIV-infected macaques, similar to that of HIV-infected individuals with neuropathy. Changes in dorsal root ganglia (DRG) included macrophage infiltration, SIV replication in macrophages, immune activation of satellite cells, and neuronal loss. To determine whether dorsal root ganglion damage was associated with altered nerve function, we measured unmyelinated C-fiber conduction velocities (CV) in nerves of SIV-infected macaques and compared CV changes with DRG alterations. Twelve weeks postinoculation, SIV-infected macaques had significantly lower C-fiber conduction velocity in sural nerves than uninfected animals and the magnitude of conduction velocity decline correlated strongly with extent of DRG macrophage infiltration. Thus, injury to neurons in the DRG-mediated by activated macrophages-preceded altered conduction of unmyelinated nerve fibers in SIV-infected macaques, suggesting that macrophage-mediated DRG damage may be the initiating event in HIV-induced sensory neuropathy.
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Castañeda Rodriguez WR, Callstrom MR. Effective Pain Palliation and Prevention of Fracture for Axial-Loading Skeletal Metastases Using Combined Cryoablation and Cementoplasty. Tech Vasc Interv Radiol 2011; 14:160-9. [DOI: 10.1053/j.tvir.2011.02.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Depression, cytokines and experimental pain: evidence for sex-related association patterns. J Affect Disord 2011; 131:143-9. [PMID: 21167607 DOI: 10.1016/j.jad.2010.11.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Revised: 11/12/2010] [Accepted: 11/12/2010] [Indexed: 12/21/2022]
Abstract
BACKGROUND There is robust evidence that altered neural-immune interactions including increased levels of proinflammatory cytokines are involved in both the pathogenesis of depression and altered pain processing. Proinflammatory cytokines induce sickness behavior, a constellation of symptoms that bears a strong similarity to those of depression. A feature of sickness behavior is enhanced pain sensitivity and it has been suggested that proinflammatory cytokines interact with pain processing directly and via several neurobiological pathways. Previous research indicates that depression and pain are closely related. We investigated the association between proinflammatory cytokines and experimental pain in major depression. METHODS Psychopathological variables, pressure pain thresholds (PPT) and concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were measured in 37 outpatients with major depression and 48 healthy controls. RESULTS Compared with controls, depressed patients exhibited significantly higher levels of TNF-α and significantly decreased PPT indicating enhanced pain sensitivity. The group differences were robust when adjusting for sex and body mass index, although sex was significantly related to PPT. No group difference was observed in IL-6. PPT correlated significantly with TNF-α in women but not in men. LIMITATIONS Because of the cross-sectional design, causality of the relation between TNF-α and pain cannot be determined. Results should be considered preliminary given the small sample size. CONCLUSION The present findings suggest that increased pain sensitivity in depression may be linked to increased TNF-α concentration. The absence of this association in men is discussed in terms of pain-related psychobiological sex differences.
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Lam DK, Schmidt BL. Orofacial pain onset predicts transition to head and neck cancer. Pain 2011; 152:1206-1209. [PMID: 21388740 PMCID: PMC3099418 DOI: 10.1016/j.pain.2011.02.009] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2010] [Revised: 01/11/2011] [Accepted: 02/02/2011] [Indexed: 12/17/2022]
Abstract
Contrary to a clinical aphorism that early head and neck cancer is painless, we show that patients who develop head and neck cancer experience significant pain at the time of initial diagnosis. We compared orofacial pain sensitivity in groups of patients with normal oral mucosa, oral precancer, and newly diagnosed oral cancer. The University of California San Francisco Oral Cancer Pain Questionnaire was administered to these patients at their initial visit, before being prescribed analgesics for pain and before any treatment. In contrast to those with biopsy-proven normal oral mucosa and oral precancer, only oral cancer patients reported significant levels of spontaneous pain and functional restriction from pain. Moreover, oral cancer patients experienced significantly higher function-related, rather than spontaneous, pain qualities. These findings suggest an important predictor for the transition from oral precancer to cancer may be the onset of orofacial pain that is exacerbated during function. Screening patients who have new-onset orofacial pain may lead to a diagnosis of early resectable head and neck cancer and may improve quality of life and survival for head and neck cancer patients.
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Affiliation(s)
- David K Lam
- Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA, USA Bluestone Center for Clinical Research, New York University, New York, NY, USA Department of Oral and Maxillofacial Surgery, New York University, New York, NY, USA
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Ruscheweyh R, Wilder-Smith O, Drdla R, Liu XG, Sandkühler J. Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Mol Pain 2011; 7:20. [PMID: 21443797 PMCID: PMC3078873 DOI: 10.1186/1744-8069-7-20] [Citation(s) in RCA: 166] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2010] [Accepted: 03/28/2011] [Indexed: 01/19/2023] Open
Abstract
Long-term potentiation (LTP) in nociceptive spinal pathways shares several features with hyperalgesia and has been proposed to be a cellular mechanism of pain amplification in acute and chronic pain states. Spinal LTP is typically induced by noxious input and has therefore been hypothesized to contribute to acute postoperative pain and to forms of chronic pain that develop from an initial painful event, peripheral inflammation or neuropathy. Under this assumption, preventing LTP induction may help to prevent the development of exaggerated postoperative pain and reversing established LTP may help to treat patients who have an LTP component to their chronic pain. Spinal LTP is also induced by abrupt opioid withdrawal, making it a possible mechanism of some forms of opioid-induced hyperalgesia. Here, we give an overview of targets for preventing LTP induction and modifying established LTP as identified in animal studies. We discuss which of the various symptoms of human experimental and clinical pain may be manifestations of spinal LTP, review the pharmacology of these possible human LTP manifestations and compare it to the pharmacology of spinal LTP in rodents.
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Affiliation(s)
- Ruth Ruscheweyh
- Department of Neurology, University of Münster, Münster, Germany
| | - Oliver Wilder-Smith
- Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Ruth Drdla
- Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Xian-Guo Liu
- Pain Research Center and Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jürgen Sandkühler
- Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
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Chen X, Pang RP, Shen KF, Zimmermann M, Xin WJ, Li YY, Liu XG. TNF-α enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury. Exp Neurol 2011; 227:279-86. [DOI: 10.1016/j.expneurol.2010.11.017] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Revised: 11/19/2010] [Accepted: 11/29/2010] [Indexed: 01/28/2023]
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Zhang H, Nei H, Dougherty PM. A p38 mitogen-activated protein kinase-dependent mechanism of disinhibition in spinal synaptic transmission induced by tumor necrosis factor-alpha. J Neurosci 2010; 30:12844-55. [PMID: 20861388 PMCID: PMC2947110 DOI: 10.1523/jneurosci.2437-10.2010] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2010] [Revised: 06/29/2010] [Accepted: 08/05/2010] [Indexed: 12/20/2022] Open
Abstract
Tumor necrosis factor-α (TNFα) is a proinflammatory cytokine that contributes to inflammatory and neuropathic pain. The mechanism by which TNFα modulates synaptic transmission in mouse substantia gelatinosa was studied using whole-cell patch clamp and immunohistochemistry. TNFα was confirmed to significantly increase the frequency of spontaneous EPSCs (sEPSCs) in spinal neurons and to also produce a robust decrease in the frequency of spontaneous IPSCs (sIPSCs). The enhancement of excitatory synaptic transmission by TNFα is in fact observed to be dependent on the suppression of sIPSCs, or disinhibition, in that blockade of inhibitory synaptic transmission prevents the effect of TNFα on sEPSCs but not vice versa. TNFα-induced inhibition of sIPSCs was blocked by neutralizing antibodies to TNF receptor 1 (TNFR1) but not to TNFR2 and was abolished by the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]. TNFα rapidly inhibited spontaneous action potentials in GABAergic neurons identified in transgenic mice expressing enhanced green fluorescent protein controlled by the GAD67 promoter. This inhibitory effect was also blocked by intracellular delivery of SB202190 to the targeted cells. The inhibition of spontaneous activity in GABAergic neurons by TNFα is shown as mediated by a reduction in the hyperpolarization-activated cation current (Ih). These results suggest a novel TNFα-TNFR1-p38 pathway in spinal GABAergic neurons that may contribute to the development of neuropathic and inflammatory pain by TNFα.
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Affiliation(s)
- Haijun Zhang
- Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030
| | - Hui Nei
- Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030
| | - Patrick M. Dougherty
- Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030
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Krenk L, Rasmussen LS, Kehlet H. New insights into the pathophysiology of postoperative cognitive dysfunction. Acta Anaesthesiol Scand 2010; 54:951-6. [PMID: 20626359 DOI: 10.1111/j.1399-6576.2010.02268.x] [Citation(s) in RCA: 198] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
There is evidence that postoperative cognitive dysfunction (POCD) is a significant problem after major surgery, but the pathophysiology has not been fully elucidated. The interpretation of available studies is difficult due to differences in neuropsychological test batteries as well as the lack of appropriate controls. Furthermore, there are no internationally accepted criteria for defining POCD. This article aims to provide an update of current knowledge of the pathogenesis of POCD with a focus on perioperative pathophysiology and possible benefits achieved from an enhanced postoperative recovery using a fast-track methodology. It is concluded that the pathogenesis of POCD is multifactorial and future studies should focus on evaluating the role of postoperative sleep disturbances, inflammatory stress responses, pain and environmental factors. Potential prophylactic intervention may include minimal invasive surgery, multi-modal non-opioid pain management and pharmacological manipulation of the inflammatory response and sleep architecture.
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Affiliation(s)
- L Krenk
- Department of Anaesthesia, Centre of Head and Orthopaedics, Rigshospitalet, Copenhagen, Denmark.
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Main LC, Dawson B, Heel K, Grove JR, Landers GJ, Goodman C. Relationship between inflammatory cytokines and self-report measures of training overload. Res Sports Med 2010; 18:127-39. [PMID: 20397115 DOI: 10.1080/15438621003627133] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
It has been purported that inflammatory cytokines may be responsible for the aetiology of overtraining. The aim of the present study was to investigate the relationship between self-reported measures of overtraining and inflammatory cytokines. Eight elite male rowers were monitored in their natural training environment for 8 weeks prior to the 2007 Rowing World Championships. During this period of intense endurance training, self-report measures of overtraining and inflammatory cytokines (Interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12p70, and Tumor Necrosis Factor (TNF)-alpha) were assessed fortnightly. Consistent with previous findings, proinflammatory cytokines IL-1beta and TNF-alpha were significantly associated (p <or= 0.05) with measures of depressed mood, sleep disturbances, and stress. Similarly, IL-6 was significantly associated (p <or= 0.01) with measures of depressed mood, sleep disturbances, and fatigue. These results are consistent with previous hypotheses describing how overtraining may be caused by excessive cytokine release, and lend further support for a cytokine hypothesis of overtraining.
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Affiliation(s)
- Luana C Main
- School of Sport Science, Exercise and Health, The University of Western Australia, Perth, Australia.
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