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1
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Layden A, Ma X, Johnson CA, He XJ, Buczynski SA, Banghart MR. A Biomimetic C-Terminal Extension Strategy for Photocaging Amidated Neuropeptides. J Am Chem Soc 2023; 145:19611-19621. [PMID: 37649440 PMCID: PMC10510324 DOI: 10.1021/jacs.3c03913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Indexed: 09/01/2023]
Abstract
Photoactivatable neuropeptides offer a robust stimulus-response relationship that can drive mechanistic studies into the physiological mechanisms of neuropeptidergic transmission. The majority of neuropeptides contain a C-terminal amide, which offers a potentially general site for installation of a C-terminal caging group. Here, we report a biomimetic caging strategy in which the neuropeptide C-terminus is extended via a photocleavable amino acid to mimic the proneuropeptides found in large dense-core vesicles. We explored this approach with four prominent neuropeptides: gastrin-releasing peptide (GRP), oxytocin (OT), substance P (SP), and cholecystokinin (CCK). C-terminus extension greatly reduced the activity of all four peptides at heterologously expressed receptors. In cell type-specific electrophysiological recordings from acute brain slices, subsecond flashes of ultraviolet light produced rapidly activating membrane currents via activation of endogenous G protein-coupled receptors. Subsequent mechanistic studies with caged CCK revealed a role for extracellular proteases in shaping the temporal dynamics of CCK signaling, and a striking switch-like, cell-autonomous anti-opioid effect of transient CCK signaling in hippocampal parvalbumin interneurons. These results suggest that C-terminus extension with a photocleavable linker may be a general strategy for photocaging amidated neuropeptides and demonstrate how photocaged neuropeptides can provide mechanistic insights into neuropeptide signaling that are inaccessible using conventional approaches.
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Affiliation(s)
| | | | - Caroline A. Johnson
- Department of Neurobiology,
School of Biological Sciences, University
of California San Diego, La Jolla, California 92093, United States
| | | | - Stanley A. Buczynski
- Department of Neurobiology,
School of Biological Sciences, University
of California San Diego, La Jolla, California 92093, United States
| | - Matthew R. Banghart
- Department of Neurobiology,
School of Biological Sciences, University
of California San Diego, La Jolla, California 92093, United States
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2
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Hou Y, Zou G, Wang X, Guo H, Ma X, Cheng X, Xie Z, Zuo X, Xia J, Mao H, Yuan M, Chen Q, Cao P, Yang Y, Zhang L, Xiong W. Coordinated activity of a central pathway drives associative opioid analgesic tolerance. SCIENCE ADVANCES 2023; 9:eabo5627. [PMID: 36753548 PMCID: PMC9908028 DOI: 10.1126/sciadv.abo5627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 12/22/2022] [Indexed: 06/18/2023]
Abstract
Opioid analgesic tolerance, a root cause of opioid overdose and misuse, can develop through an associative learning. Despite intensive research, the locus and central pathway subserving the associative opioid analgesic tolerance (AOAT) remains unclear. Using a combination of chemo/optogenetic manipulation with calcium imaging and slice physiology, here we identify neuronal ensembles in a hierarchically organized pathway essential for AOAT. The association of morphine-induced analgesia with an environmental condition drives glutamatergic signaling from ventral hippocampus (vHPC) to dorsomedial prefrontal cortex (dmPFC) cholecystokininergic (CCKergic) neurons. Excitation of CCKergic neurons, which project and release CCK to basolateral amygdala (BLA) glutamatergic neurons, relays AOAT signal through inhibition of BLA μ-opioid receptor function, thereby leading to further loss of morphine analgesic efficacy. This work provides evidence for a circuit across different brain regions distinct for opioid analgesic tolerance. The components of this pathway are potential targets to treat opioid overdose and abuse.
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Affiliation(s)
- Yiwen Hou
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
| | - Guichang Zou
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
- Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei 230088, China
| | - Xianglian Wang
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
| | - Hui Guo
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
| | - Xiao Ma
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
| | - Xingyu Cheng
- National Institute of Biological Sciences, Beijing 102206, China
| | - Zhiyong Xie
- National Institute of Biological Sciences, Beijing 102206, China
| | - Xin Zuo
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
| | - Jing Xia
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
| | - Huanhuan Mao
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
| | - Man Yuan
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
| | - Qi Chen
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
| | - Peng Cao
- National Institute of Biological Sciences, Beijing 102206, China
| | - Yupeng Yang
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
| | - Li Zhang
- Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Wei Xiong
- Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
- Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei 230088, China
- Anhui Province Key Laboratory of Biomedical Aging Research, Hefei 230026, China
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3
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CCK2 receptors in chronic pain. NEUROBIOLOGY OF PAIN 2022; 11:100092. [PMID: 35571964 PMCID: PMC9097710 DOI: 10.1016/j.ynpai.2022.100092] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/22/2022] [Accepted: 05/02/2022] [Indexed: 11/21/2022]
Abstract
CCK2R is a historic target for pain management that has shown limited success. We review CCK2Rs and their role in peripheral and central circuits in chronic pain. We discuss the interactions between CCK2Rs and opioids. We highlight recent drug discovery efforts targeting CCK2R for chronic pain. The cholecystokinin receptor system, specifically cholecystokinin 2 receptor (CCK2R) is a historic target for pain management that has shown limited success. However, new approaches to target CCK2R have incited fresh enthusiasm for this target. In this mini-review, we discuss what is known about CCK2R in peripheral and central circuits under naïve physiological conditions and under conditions of chronic pain, the interactions of CCK2Rs with opioids and briefly, recent efforts to develop new treatments targeting CCK2R for chronic pain.
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4
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Kaczyńska K, Wojciechowski P. Non-Opioid Peptides Targeting Opioid Effects. Int J Mol Sci 2021; 22:13619. [PMID: 34948415 PMCID: PMC8709238 DOI: 10.3390/ijms222413619] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/13/2021] [Accepted: 12/17/2021] [Indexed: 01/07/2023] Open
Abstract
Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as tolerance, addiction, respiratory depression, and cardiovascular events. This, in turn, can result in their overuse in cases of addiction, the need for dose escalation in cases of developing tolerance, and the emergence of dose-related opioid toxicity, resulting in respiratory depression or cardiovascular problems that can even lead to unintentional death. Therefore, a very important challenge for researchers is to look for ways to counteract the side effects of opioids. The use of peptides and their related compounds, which have been shown to modulate the effects of opioids, may provide such an opportunity. This short review is a compendium of knowledge about the most important and recent findings regarding selected peptides and their modulatory effects on various opioid actions, including cardiovascular and respiratory responses. In addition to the peptides more commonly reported in the literature in the context of their pro- and/or anti-opioid activity-such as neuropeptide FF (NPFF), cholecystokinin (CCK), and melanocyte inhibiting factor (MIF)-we also included in the review nociceptin/orphanin (N/OFQ), ghrelin, oxytocin, endothelin, and venom peptides.
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Affiliation(s)
- Katarzyna Kaczyńska
- Department of Respiration Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5 St., 02-106 Warsaw, Poland;
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5
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The Cholecystokinin Type 2 Receptor, a Pharmacological Target for Pain Management. Pharmaceuticals (Basel) 2021; 14:ph14111185. [PMID: 34832967 PMCID: PMC8618735 DOI: 10.3390/ph14111185] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
Over the past decades, accumulating evidence has demonstrated a pivotal role of cholecystokinin type 2 receptor (CCK2R) in pain modulation. The established role of CCK2R activation in directly facilitating nociception has led to the development of several CCK2R antagonists, which have been shown to successfully alleviate pain in several rodent models of pain. However, the outcomes of clinical trials are more modest since they have not demonstrated the expected biological effect obtained in animals. Such discordances of results between preclinical and clinical studies suggest reconsidering our knowledge about the molecular basis of the pharmacology and functioning of CCK2R. This review focuses on the cellular localization of CCK2R specifically in the sensory nervous system and discusses in further detail the molecular mechanisms and signal transduction pathways involved in controlling pain perception. We then provide a comprehensive overview of the most successful compounds targeting CCK2R and report recent advances in pharmacological strategies used to achieve CCK2R modulation. We purposely distinguish between CCK2R benefits obtained in preclinical models and outcomes in clinical trials with different pain etiologies. Lastly, we emphasize the biological and clinical relevance of CCK2R as a promising target for the development of new treatments for pain management.
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6
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Wercberger R, Braz JM, Weinrich JA, Basbaum AI. Pain and itch processing by subpopulations of molecularly diverse spinal and trigeminal projection neurons. Proc Natl Acad Sci U S A 2021; 118:e2105732118. [PMID: 34234018 PMCID: PMC8285968 DOI: 10.1073/pnas.2105732118] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
A remarkable molecular and functional heterogeneity of the primary sensory neurons and dorsal horn interneurons transmits pain- and or itch-relevant information, but the molecular signature of the projection neurons that convey the messages to the brain is unclear. Here, using retro-TRAP (translating ribosome affinity purification) and RNA sequencing, we reveal extensive molecular diversity of spino- and trigeminoparabrachial projection neurons. Among the many genes identified, we highlight distinct subsets of Cck+ -, Nptx2+ -, Nmb+ -, and Crh+ -expressing projection neurons. By combining in situ hybridization of retrogradely labeled neurons with Fos-based assays, we also demonstrate significant functional heterogeneity, including both convergence and segregation of pain- and itch-provoking inputs into molecularly diverse subsets of NK1R- and non-NK1R-expressing projection neurons.
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Affiliation(s)
- Racheli Wercberger
- Department of Anatomy, University of California, San Francisco, CA 94158
| | - Joao M Braz
- Department of Anatomy, University of California, San Francisco, CA 94158
| | - Jarret A Weinrich
- Department of Anatomy, University of California, San Francisco, CA 94158
| | - Allan I Basbaum
- Department of Anatomy, University of California, San Francisco, CA 94158
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7
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Serafin EK, Paranjpe A, Brewer CL, Baccei ML. Single-nucleus characterization of adult mouse spinal dynorphin-lineage cells and identification of persistent transcriptional effects of neonatal hindpaw incision. Pain 2021; 162:203-218. [PMID: 33045156 PMCID: PMC7744314 DOI: 10.1097/j.pain.0000000000002007] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Neonatal tissue damage can have long-lasting effects on nociceptive processing in the central nervous system, which may reflect persistent injury-evoked alterations to the normal balance between synaptic inhibition and excitation in the spinal dorsal horn. Spinal dynorphin-lineage (pDyn) neurons are part of an inhibitory circuit which limits the flow of nociceptive input to the brain and is disrupted by neonatal tissue damage. To identify the potential molecular underpinnings of this disruption, an unbiased single-nucleus RNAseq analysis of adult mouse spinal pDyn cells characterized this population in depth and then identified changes in gene expression evoked by neonatal hindpaw incision. The analysis revealed 11 transcriptionally distinct subpopulations (ie, clusters) of dynorphin-lineage cells, including both inhibitory and excitatory neurons. Investigation of injury-evoked differential gene expression identified 15 genes that were significantly upregulated or downregulated in adult pDyn neurons from neonatally incised mice compared with naive littermate controls, with both cluster-specific and pan-neuronal transcriptional changes observed. Several of the identified genes, such as Oxr1 and Fth1 (encoding ferritin), were related to the cellular stress response. However, the relatively low number of injury-evoked differentially expressed genes also suggests that posttranscriptional regulation within pDyn neurons may play a key role in the priming of developing nociceptive circuits by early-life injury. Overall, the findings reveal novel insights into the molecular heterogeneity of a key population of dorsal horn interneurons that has previously been implicated in the suppression of mechanical pain and itch.
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Affiliation(s)
- Elizabeth K Serafin
- Department of Anesthesiology, Pain Research Center, University of Cincinnati Medical Center, Cincinnati, OH, United States . Dr. Brewer is now with the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
| | - Aditi Paranjpe
- Division of Biomedical Informatics, Bioinformatics Collaborative Services, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Chelsie L Brewer
- Department of Anesthesiology, Pain Research Center, University of Cincinnati Medical Center, Cincinnati, OH, United States . Dr. Brewer is now with the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
- Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Mark L Baccei
- Department of Anesthesiology, Pain Research Center, University of Cincinnati Medical Center, Cincinnati, OH, United States . Dr. Brewer is now with the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
- Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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8
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Multifunctional Opioid-Derived Hybrids in Neuropathic Pain: Preclinical Evidence, Ideas and Challenges. Molecules 2020; 25:molecules25235520. [PMID: 33255641 PMCID: PMC7728063 DOI: 10.3390/molecules25235520] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/22/2020] [Accepted: 11/23/2020] [Indexed: 12/21/2022] Open
Abstract
When the first- and second-line therapeutics used to treat neuropathic pain (NP) fail to induce efficient analgesia—which is estimated to relate to more than half of the patients—opioid drugs are prescribed. Still, the pathological changes following the nerve tissue injury, i.a. pronociceptive neuropeptide systems activation, oppose the analgesic effects of opiates, enforcing the use of relatively high therapeutic doses in order to obtain satisfying pain relief. In parallel, the repeated use of opioid agonists is associated with burdensome adverse effects due to compensatory mechanisms that arise thereafter. Rational design of hybrid drugs, in which opioid ligands are combined with other pharmacophores that block the antiopioid action of pronociceptive systems, delivers the opportunity to ameliorate the NP-oriented opioid treatment via addressing neuropathological mechanisms shared both by NP and repeated exposition to opioids. Therewith, the new dually acting drugs, tailored for the specificity of NP, can gain in efficacy under nerve injury conditions and have an improved safety profile as compared to selective opioid agonists. The current review presents the latest ideas on opioid-comprising hybrid drugs designed to treat painful neuropathy, with focus on their biological action, as well as limitations and challenges related to this therapeutic approach.
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9
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Gibula-Tarlowska E, Kotlinska JH. Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance. Biomolecules 2020; 10:E1376. [PMID: 32998249 PMCID: PMC7599993 DOI: 10.3390/biom10101376] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/20/2020] [Accepted: 09/23/2020] [Indexed: 12/23/2022] Open
Abstract
Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense long-term investigations. Such studies indicate that some endogenous neuropeptides, called anti-opioids, participate in a homeostatic system that tends to reduce the effects of endogenous and exogenous opioids. Anti-opioid properties have been attributed to various peptides, including melanocyte inhibiting factor (MIF)-related peptides, cholecystokinin (CCK), nociceptin/orphanin FQ (N/OFQ), and neuropeptide FF (NPFF). These peptides counteract some of the acute effects of opioids, and therefore, they are involved in the development of opioid tolerance and addiction. In this work, the anti-opioid profile of endogenous peptides was described, mainly taking into account their inhibitory influence on opioid-induced effects. However, the anti-opioid peptides demonstrated complex properties and could show opioid-like as well as anti-opioid effects. The aim of this review is to detail the phenomenon of crosstalk taking place between opioid and anti-opioid systems at the in vivo pharmacological level and to propose a cellular and molecular basis for these interactions. A better knowledge of these mechanisms has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.
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Affiliation(s)
- Ewa Gibula-Tarlowska
- Department of Pharmacology and Pharmacodynamics, Medical University, 20-059 Lublin, Poland;
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10
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Wercberger R, Basbaum AI. Spinal cord projection neurons: a superficial, and also deep, analysis. CURRENT OPINION IN PHYSIOLOGY 2019; 11:109-115. [PMID: 32864531 DOI: 10.1016/j.cophys.2019.10.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Today there are extensive maps of the molecular heterogeneity of primary afferents and dorsal horn interneurons, yet there is a dearth of molecular and functional information regarding the projection neurons that transmit pain and itch information to the brain. Additionally, most contemporary research into the spinal cord and medullary projection neurons focuses on neurons in the superficial dorsal horn; the contribution of deep dorsal horn and even ventral horn projection neurons to pain and itch processing is often overlooked. In the present review we integrate conclusions from classical as well as contemporary studies and provide a more balanced view of the diversity of projection neurons. A major question addressed is the extent to which labeled-lines are maintained in these different populations or whether the brain generates distinct pain and itch percepts by decoding complex convergent inputs that engage projection neurons.
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Affiliation(s)
- Racheli Wercberger
- Department of Anatomy and Neuroscience Graduate Program, University California San Francisco, San Francisco, CA 94158
| | - Allan I Basbaum
- Department of Anatomy and Neuroscience Graduate Program, University California San Francisco, San Francisco, CA 94158
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11
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Abstract
Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use of opioids is frequently associated with the occurrence of adverse effects or clinical problems. Other than adverse effects and dependence, the development of tolerance is a significant problem, as it requires increased opioid drug doses to achieve the same effect. Mechanisms of opioid tolerance include drug-induced adaptations or allostatic changes at the cellular, circuitry, and system levels. Dose escalation in long-term opioid therapy might cause opioid-induced hyperalgesia (OIH), which is a state of hypersensitivity to painful stimuli associated with opioid therapy, resulting in exacerbation of pain sensation rather than relief of pain. Various strategies may provide extra-opioid analgesia. There are drugs that may produce independent analgesic effects. A tailored treatment provided by skilled personnel, in accordance with the individual condition, is mandatory. Any treatment aimed at reducing opioid consumption may be indicated in these circumstances. Interventional techniques able to decrease the pain input may allow a decrease in the opioid dose, thus reverting the mechanisms producing tolerance of OIH. Intrathecal therapy with local anesthetics and a sympathetic block are the most common techniques utilized in these circumstances.
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Affiliation(s)
- Sebastiano Mercadante
- Main Regional Center of Supportive/Palliative Care, La Maddalena Cancer Center, Palermo, Italy.
- Palliative/Supportive Care and Rehabilitation, MD Anderson, Houston, TX, USA.
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12
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Gley K, Murani E, Trakooljul N, Zebunke M, Puppe B, Wimmers K, Ponsuksili S. Transcriptome profiles of hypothalamus and adrenal gland linked to haplotype related to coping behavior in pigs. Sci Rep 2019; 9:13038. [PMID: 31506580 PMCID: PMC6736951 DOI: 10.1038/s41598-019-49521-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Accepted: 08/27/2019] [Indexed: 11/08/2022] Open
Abstract
The hypothalamic-pituitary-adrenal (HPA) axis is an important component of neuroendocrine stress regulation and coping behavior. Transcriptome profiles of the hypothalamus and adrenal gland were assessed to identify molecular pathways and candidate genes for coping behavior in pigs. Ten each of high- (HR) and low- (LR) reactive pigs (n = 20) were selected for expression profiling based haplotype information of a prominent QTL-region on SSC12 discovered in our previous genome-wide association study (GWAS) on coping behavior. Comparing the HR and LR pigs showed 692 differentially expressed genes (DEGs) in the adrenal gland and 853 DEGs in the hypothalamus, respectively. Interestingly, 47% (17 out of 36) of DEGs found in both tissues were located in GWAS regions identified on SSC12, indicating that there are significant functional positional candidate genes for coping behaviour. Pathway analysis assigned DEGs to glucocorticoid receptor signaling in the adrenal gland. Furthermore, oxidative phosphorylation, mitochondrial dysfunction, and NGF signaling as well as cholecystokinin/Gastrin-mediated were identified in the hypothalamus. We narrowed the list of candidate genes in GWAS regions by analyzing their DEGs in the HPA axis. The top identified transcripts, including ATP1B2, AURKB, MPDU1 and NDEL1 provide evidence for molecular correlates of coping behavior in GWAS regions.
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Affiliation(s)
- Kevin Gley
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, D-18196, Dummerstorf, Germany
| | - Eduard Murani
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, D-18196, Dummerstorf, Germany
| | - Nares Trakooljul
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, D-18196, Dummerstorf, Germany
| | - Manuela Zebunke
- Leibniz Institute for Farm Animal Biology (FBN), Institute of Genetics and Biometry, Wilhelm-Stahl-Allee 2, D-18196, Dummerstorf, Germany
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Behavioral Physiology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Birger Puppe
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Behavioral Physiology, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Klaus Wimmers
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, D-18196, Dummerstorf, Germany
| | - Siriluck Ponsuksili
- Leibniz Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, D-18196, Dummerstorf, Germany.
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13
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Hruby VJ. Multivalent peptide and peptidomimetic ligands for the treatment of pain without toxicities and addiction. Peptides 2019; 116:63-67. [PMID: 31014958 DOI: 10.1016/j.peptides.2019.02.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 02/09/2019] [Accepted: 02/13/2019] [Indexed: 12/14/2022]
Abstract
The current opioid crisis has created a tragic problem in medicine and society. Pain is the most ubiquitous and costly disease in society and yet all of our "treatments" have toxicities, especially for prolonged use. However, there are several alternatives that have been discovered in the past fifteen years that have been demonstrated in animals to have none of the toxicities of current drugs. Many of the compounds are multivalent and have novel biological activity profiles. Unfortunately, none of these have been in clinical trials in humans, perhaps because they were discovered in academic laboratories. A review of these novel chemicals are given in this paper.
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MESH Headings
- Analgesics, Opioid/therapeutic use
- Animals
- Humans
- Ligands
- Opioid Peptides/chemistry
- Opioid Peptides/therapeutic use
- Pain/drug therapy
- Pain/pathology
- Pain Management
- Peptides/adverse effects
- Peptides/therapeutic use
- Peptidomimetics/adverse effects
- Peptidomimetics/therapeutic use
- Receptors, Opioid/chemistry
- Receptors, Opioid/therapeutic use
- Receptors, Opioid, delta/chemistry
- Receptors, Opioid, delta/genetics
- Receptors, Opioid, mu/chemistry
- Receptors, Opioid, mu/genetics
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Affiliation(s)
- Victor J Hruby
- Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, 85721, USA
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14
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15
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Yang Y, Li Q, He QH, Han JS, Su L, Wan Y. Heteromerization of μ-opioid receptor and cholecystokinin B receptor through the third transmembrane domain of the μ-opioid receptor contributes to the anti-opioid effects of cholecystokinin octapeptide. Exp Mol Med 2018; 50:1-16. [PMID: 29780163 PMCID: PMC5960647 DOI: 10.1038/s12276-018-0090-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 01/21/2018] [Accepted: 03/06/2018] [Indexed: 11/08/2022] Open
Abstract
Activation of the cholecystokinin type B receptor (CCKBR) by cholecystokinin octapeptide (CCK-8) inhibits opioid analgesia. Chronic opiate treatment leads to an increase in the CCK-8 concentration and thus enhances the antagonism of CCK-8 against opioid analgesia; the underlying molecular mechanisms remain of great interest. In the present study, we validated the colocalization of the μ-opioid receptor (MOR) and CCKBR in pain signal transmission-related spinal cord dorsal horn and dorsal root ganglion neurons of rats. Co-immunoprecipitation (Co-IP) and fluorescence lifetime-imaging-microscopy-based fluorescence resonance energy transfer (FLIM-FRET) assays showed that MOR heteromerized with CCKBR directly in transfected HEK293 cells. Combined with MOR mutant construction, the third transmembrane domain of MOR (TM3MOR) was demonstrated to participate in heteromerization with CCKBR. Receptor ligand binding, ERK phosphorylation and cAMP assays showed that MOR heteromerization with CCKBR weakened the activity of MOR. A cell-penetrating interfering peptide consisting of TM3MOR and TAT (a transactivator of HIV-1) sequences from the N terminal to the C terminal disrupted the MOR-CCKBR interaction and restored the activity of MOR in transfected HEK293 cells. Furthermore, intrathecal application of the TM3MOR-TAT peptide alleviated CCK-8-injection-induced antagonism to morphine analgesia in rats. These results suggest a new molecular mechanism for CCK-8 antagonism to opioid analgesia in terms of G-protein-coupled receptor (GPCR) interaction through direct heteromerization. Our study may provide a potential strategy for pain management with opioid analgesics.
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Affiliation(s)
- Yin Yang
- Neuroscience Research Institute, Peking University, Beijing, 100083, P. R. China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, 100083, P. R. China
| | - Qian Li
- Neuroscience Research Institute, Peking University, Beijing, 100083, P. R. China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, 100083, P. R. China
| | - Qi-Hua He
- Center of Medical and Health Analysis, Peking University, Beijing, 100083, P. R. China
| | - Ji-Sheng Han
- Neuroscience Research Institute, Peking University, Beijing, 100083, P. R. China
- Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, 100083, P. R. China
- Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, 100083, P. R. China
| | - Li Su
- Center of Medical and Health Analysis, Peking University, Beijing, 100083, P. R. China.
| | - You Wan
- Neuroscience Research Institute, Peking University, Beijing, 100083, P. R. China.
- Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, 100083, P. R. China.
- Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, 100083, P. R. China.
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Hao L, Wen D, Gou H, Yu F, Cong B, Ma C. Over-expression of CCK1 Receptor Reverse Morphine Dependence. Int J Pept Res Ther 2018; 24:471-477. [PMID: 30147637 PMCID: PMC6096524 DOI: 10.1007/s10989-018-9696-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2018] [Indexed: 12/30/2022]
Abstract
Studies demonstrated that cholecystokinin (CCK) system involved in morphine dependence and withdrawal. Our previous study showed that endogenous CCK system were up-regulated after chronic morphine exposure. Additionally, CCK1 receptor significantly blocked the inhibitory effect of exogenous CCK-8 on morphine dependence, but CCK2 receptor appears to be necessary for low concentrations of endogenous CCK to potentiate morphine dependence. Therefore, CCK1R and CCK2R function differently in chronic morphine dependence, but the mechanism is still unclear. In this study, HEK-293 cells co-transfected with µ-opioid receptors (HEK293-hMOR) and CCK1R or CCK2R were established. Cells were treated with 10 µM morphine for 6, 12, 16, 24 h and 100 µM naloxone precipitation for 15 min. cAMP overshoot was appeared at 12 h and was increased time dependently after morphine exposure in HEK293-hMOR cells. The cAMP overshoot did not appear in CCK1R-overexpressing HEK293-hMOR cells, while still appeared in CCK2R-overexpressing HEK293-hMOR cells. Over-expression of CCK1R reversed CREB and ERK1/2 activation in HEK293-hMOR cells exposed to morphine. Our study identifies over-expression of CCK1R significantly blocked morphine dependence, which was related with phosphorylation of CREB, and ERK1/2 signaling activation. While over-expression of CCK2R promoted morphine dependence, which was related with phosphorylation of CREB but not ERK1/2 signaling activation.
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Affiliation(s)
- Lijing Hao
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China.,2Department of Anesthesiology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, 050051 People's Republic of China
| | - Di Wen
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China
| | - Hongyan Gou
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China.,CUHK Shenzhen Research Institute, 2 Yuexing Road, Nanshan District, Shenzhen, 518057 People's Republic of China
| | - Feng Yu
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China
| | - Bin Cong
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China
| | - Chunling Ma
- 1Department of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, 050017 Hebei Province People's Republic of China
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17
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Calisi RM, Austin SH, Lang AS, MacManes MD. Sex-biased transcriptomic response of the reproductive axis to stress. Horm Behav 2018; 100:56-68. [PMID: 29378207 DOI: 10.1016/j.yhbeh.2017.11.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 11/16/2017] [Accepted: 11/17/2017] [Indexed: 02/07/2023]
Abstract
Stress is a well-known cause of reproductive dysfunction in many species, including birds, rodents, and humans, though males and females may respond differently. A powerful way to investigate how stress affects reproduction is by examining its effects on a biological system essential for regulating reproduction, the hypothalamic-pituitary-gonadal (HPG) axis. Often this is done by observing how a stressor affects the amount of glucocorticoids, such as cortisol or corticosterone, circulating in the blood and their relationship with a handful of known HPG-producing reproductive hormones, like testosterone and estradiol. Until now, we have lacked a full understanding of how stress affects all genomic activity of the HPG axis and how this might differ between the sexes. We leveraged a highly replicated and sex-balanced experimental approach to test how male and female rock doves (Columba livia) respond to restraint stress at the level of their transcriptome. Females exhibit increased genomic responsiveness to stress at all levels of their HPG axis as compared to males, and these responsive genes are mostly unique to females. Reasons for this may be due to fluctuations in the female endocrine environment over the reproductive cycle and/or their evolutionary history, including parental investment and the potential for maternal effects. Direct links between genome to phenome cause and effect cannot be ascertained at this stage; however, the data we report provide a vital genomic foundation on which sex-specific reproductive dysfunction and adaptation in the face of stress can be further experimentally studied, as well as novel gene targets for genetic intervention and therapy investigations.
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Affiliation(s)
- Rebecca M Calisi
- Department of Neurobiology, Physiology and Behavior, University of California, Davis, United States.
| | - Suzanne H Austin
- Department of Neurobiology, Physiology and Behavior, University of California, Davis, United States
| | - Andrew S Lang
- Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, United States
| | - Matthew D MacManes
- Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, United States
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18
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Burgos A, Honjo K, Ohyama T, Qian CS, Shin GJE, Gohl DM, Silies M, Tracey WD, Zlatic M, Cardona A, Grueber WB. Nociceptive interneurons control modular motor pathways to promote escape behavior in Drosophila. eLife 2018. [PMID: 29528286 PMCID: PMC5869015 DOI: 10.7554/elife.26016] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Rapid and efficient escape behaviors in response to noxious sensory stimuli are essential for protection and survival. Yet, how noxious stimuli are transformed to coordinated escape behaviors remains poorly understood. In Drosophila larvae, noxious stimuli trigger sequential body bending and corkscrew-like rolling behavior. We identified a population of interneurons in the nerve cord of Drosophila, termed Down-and-Back (DnB) neurons, that are activated by noxious heat, promote nociceptive behavior, and are required for robust escape responses to noxious stimuli. Electron microscopic circuit reconstruction shows that DnBs are targets of nociceptive and mechanosensory neurons, are directly presynaptic to pre-motor circuits, and link indirectly to Goro rolling command-like neurons. DnB activation promotes activity in Goro neurons, and coincident inactivation of Goro neurons prevents the rolling sequence but leaves intact body bending motor responses. Thus, activity from nociceptors to DnB interneurons coordinates modular elements of nociceptive escape behavior.
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Affiliation(s)
- Anita Burgos
- Department of Neuroscience, Columbia University Medical Center, New York, United States
| | - Ken Honjo
- Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan
| | - Tomoko Ohyama
- Department of Biology, McGill University, Montreal, Canada
| | - Cheng Sam Qian
- Department of Neuroscience, Columbia University Medical Center, New York, United States
| | - Grace Ji-Eun Shin
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
| | - Daryl M Gohl
- University of Minnesota Genomics Center, Minneapolis, United States
| | - Marion Silies
- European Neuroscience Institute Göttingen, Göttingen, Germany
| | - W Daniel Tracey
- The Linda and Jack Gill Center for Biomolecular Science, Indiana University, Bloomington, United States.,Department of Biology, Indiana University, Bloomington, United States
| | - Marta Zlatic
- Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
| | - Albert Cardona
- Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
| | - Wesley B Grueber
- Department of Neuroscience, Columbia University Medical Center, New York, United States.,Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States.,Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, United States
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19
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Suarez-Mendez S, Tovilla-Zarate CA, Ortega-Varela LF, Bermudez-Ocaña DY, Blé-Castillo JL, González-Castro TB, Zetina-Esquivel AM, Diaz-Zagoya JC, Esther Juárez-Rojop I. Isobolographic Analyses of Proglumide-Celecoxib Interaction in Rats with Painful Diabetic Neuropathy. Drug Dev Res 2017; 78:116-123. [DOI: 10.1002/ddr.21382] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 03/08/2017] [Indexed: 12/24/2022]
Affiliation(s)
- Samuel Suarez-Mendez
- Division Académica de Ciencias de la Salud; Universidad Juárez Autónoma de Tabasco; Villahermosa Tabasco México
| | - Carlos A. Tovilla-Zarate
- Division Académica Multidisciplinaria de Comalcalco; Universidad Juárez Autónoma de Tabasco; Tabasco México
| | - Luis F. Ortega-Varela
- Escuela de Enfermería y Salud Pública; Universidad Michoacana de San Nicolás de Hidalgo; Morelia Michoacán México
| | - Deysi Y. Bermudez-Ocaña
- Division Académica Multidisciplinaria de Comalcalco; Universidad Juárez Autónoma de Tabasco; Tabasco México
| | - Jorge L. Blé-Castillo
- Division Académica de Ciencias de la Salud; Universidad Juárez Autónoma de Tabasco; Villahermosa Tabasco México
| | - Thelma B. González-Castro
- Division Académica Multidisciplinaria de Jalpa de Méndez; Universidad Juárez Autónoma de Tabasco; Tabasco México
| | - Alma M. Zetina-Esquivel
- Division Académica de Ciencias de la Salud; Universidad Juárez Autónoma de Tabasco; Villahermosa Tabasco México
| | - Juan C. Diaz-Zagoya
- Departamento de Bioquímica; Facultad de Medicina, UNAM; Ciudad de México México
| | - Isela Esther Juárez-Rojop
- Division Académica de Ciencias de la Salud; Universidad Juárez Autónoma de Tabasco; Villahermosa Tabasco México
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20
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Anyetei-Anum EN, Blum A, Seidah NG, Beinfeld MC. Prohormone convertase 7 is necessary for the normal processing of cholecystokinin in mouse brain. Biochem Biophys Res Commun 2016; 482:1190-1193. [PMID: 27923657 DOI: 10.1016/j.bbrc.2016.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 12/02/2016] [Indexed: 10/20/2022]
Abstract
Endoproteases in the secretory pathway process pro-cholecystokinin (CCK) into the biologically active forms found in the tissues that express CCK mRNA. Thus far, the endoproteases involved in CCK processing include cathepsin L and the prohormone convertases (PC) 1, 2, and 5. This study finds that PC7 is also critical for normal production of CCK in specific areas of the brain. Loss of PC7 results in decreased levels of CCK in more brain regions than any other endoprotease studied to date. Substantial decreases in brain levels of CCK are found in the prefrontal, frontal, parietal-insular-pyriform, and temporal cortex, caudate-putamen, basal forebrain, thalamus, hippocampus, septum, and medulla of PC7 knock-out (KO) mice. A tissue-specific sexual dimorphism of PC7 activity was also identified. This is the first report that loss of PC7 alters levels of a neuropeptide in the brain. This loss of PC7 and CCK may independently contribute to the decrease in Brain Derived Neurotrophic Factor production and be partially responsible for the learning and memory defects observed in mice that lack PC7.
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Affiliation(s)
- Emmanuel N Anyetei-Anum
- Pharmacology and Experimental Therapeutics, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, 02111, USA
| | - Alissa Blum
- Pharmacology and Experimental Therapeutics, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, 02111, USA
| | - Nabil G Seidah
- Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, Montréal, QC, H2W1R7, Canada
| | - Margery C Beinfeld
- Pharmacology and Experimental Therapeutics, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, 02111, USA.
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21
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Zhang D, Li H, Geng J, Li Y, Li S, Ma C, Cong B, Zhang X. The therapeutic effects of cholecystokinin octapeptide on rat liver and kidney microcirculation disorder in endotoxic shock. Immunopharmacol Immunotoxicol 2016; 39:2-10. [DOI: 10.1080/08923973.2016.1255225] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Dong Zhang
- College of Integrated Traditional and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, PR China
| | - Hui Li
- Department of Forensic Medicine, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, PR China
| | - Jing Geng
- Department of Forensic Medicine, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, PR China
| | - Yingmin Li
- Department of Forensic Medicine, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, PR China
| | - Shujin Li
- Department of Forensic Medicine, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, PR China
| | - Chunling Ma
- Department of Forensic Medicine, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, PR China
| | - Bin Cong
- Department of Forensic Medicine, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, PR China
| | - Xiaojing Zhang
- Department of Forensic Medicine, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, PR China
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22
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Influences of CCK-8 on expressions of apoptosis-related genes in prefrontal cortex neurons of morphine-relapse rats. Neurosci Lett 2016; 631:115-121. [PMID: 27544013 DOI: 10.1016/j.neulet.2016.08.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 08/09/2016] [Accepted: 08/15/2016] [Indexed: 12/15/2022]
Abstract
In order to elucidate the influences of CCK-8 on expressions of apoptosis-related genes, Bax, Bcl-2 and Caspase-3, of prefrontal cortex neurons in morphine-relapse rats, an effective, successful morphine-relapse-rat model using the conditioned place preference (CPP) under CCK-8 (0.01, 0.1 and 1.0μg, i.c.v) intervention was established. The prefrontal cortexes were made into slices with the cellular plasmas immunohistochemically stained. The expressions of Bax, Bcl-2, Caspase-3 of neurons were evaluated through their scores, and each corresponding ratio of Bax and Bcl-2 (Bax/Bcl-2) was also computed. The results showed that the expression of Bcl-2 was very weak and those of Bax and Caspase-3 were hardly seen in group normal saline; the expressions of Bax and Caspase-3 were strong and that of Bcl-2 was weak in group morphine and compared to group normal saline, there were significant differences (P<0.05); the expressions of Bax, Caspase-3 and the ratios of Bax/Bcl-2 have a gradually-decreased trend in the sequence of group 0.01μg, group 0.1μg and group 1.0μg, but the expression of Bcl-2 has an opposite trend in the same sequence, and compared to group morphine, there were significant differences (P<0.05) excluding group 0.01μg. So we draw a conclusion that CCK-8 (0.1 and 1.0μg, i.c.v) could protect neurons of prefrontal cortex through up-regulating the expression of Bcl-2, down-regulating those of Bax and Caspase-3 and reducing Bax/Bcl-2 ratio in the model of morphine-relapse rats.
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Roeckel LA, Le Coz GM, Gavériaux-Ruff C, Simonin F. Opioid-induced hyperalgesia: Cellular and molecular mechanisms. Neuroscience 2016; 338:160-182. [PMID: 27346146 DOI: 10.1016/j.neuroscience.2016.06.029] [Citation(s) in RCA: 273] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 06/10/2016] [Accepted: 06/16/2016] [Indexed: 12/18/2022]
Abstract
Opioids produce strong analgesia but their use is limited by a paradoxical hypersensitivity named opioid-induced hyperalgesia (OIH) that may be associated to analgesic tolerance. In the last decades, a significant number of preclinical studies have investigated the factors that modulate OIH development as well as the cellular and molecular mechanisms underlying OIH. Several factors have been shown to influence OIH including the genetic background and sex differences of experimental animals as well as the opioid regimen. Mu opioid receptor (MOR) variants and interactions of MOR with different proteins were shown important. Furthermore, at the cellular level, both neurons and glia play a major role in OIH development. Several neuronal processes contribute to OIH, like activation of neuroexcitatory mechanisms, long-term potentiation (LTP) and descending pain facilitation. Increased nociception is also mediated by neuroinflammation induced by the activation of microglia and astrocytes. Neurons and glial cells exert synergistic effects, which contribute to OIH. The molecular actors identified include the Toll-like receptor 4 and the anti-opioid systems as well as some other excitatory molecules, receptors, channels, chemokines, pro-inflammatory cytokines or lipids. This review summarizes the intracellular and intercellular pathways involved in OIH and highlights some mechanisms that may be challenged to limit OIH in the future.
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Affiliation(s)
- Laurie-Anne Roeckel
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Université de Strasbourg, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
| | - Glenn-Marie Le Coz
- Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Illkirch, France
| | - Claire Gavériaux-Ruff
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Université de Strasbourg, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Ecole Supérieure de Biotechnologie de Strasbourg, Université de Strasbourg, France
| | - Frédéric Simonin
- Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS, Université de Strasbourg, Illkirch, France.
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24
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Cadoni C. Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction. Front Neurosci 2016; 10:13. [PMID: 26903787 PMCID: PMC4746315 DOI: 10.3389/fnins.2016.00013] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 01/11/2016] [Indexed: 01/02/2023] Open
Abstract
Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40–60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant deviations in reward and motivational functions.
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Affiliation(s)
- Cristina Cadoni
- Institute of Neuroscience, Cagliari Section, Department of Biomedical Sciences, National Research Council of ItalyCagliari, Italy; Centre of Excellence "Neurobiology of Dependence", University of CagliariCagliari, Italy
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Abstract
BACKGROUND Monodrug therapy has been used with success to fight various pathologies. When one medicine fails, co-administration of two or more drugs at the same time may be successfully applied in the treatment of infections, hypertension, HIV and in many other fields. DISCUSSION This approach has some weakness related to the pharmacokinetic of the two different substances administered, side effects, possible drug-drug interaction. Bivalent ligand approach would maintain the strength of the multidrug therapy (synergistic effect, lower doses, and little side effects) and overcome the weakness of a co-administration. CONCLUSION In this review we have described the state-of-the-art of the multitarget approach for the control of pain. Several approaches adopted by different research groups and future perspectives have been discussed.
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Thomas J, Mustafa S, Johnson J, Nicotra L, Hutchinson M. The relationship between opioids and immune signalling in the spinal cord. Handb Exp Pharmacol 2015; 227:207-238. [PMID: 25846621 DOI: 10.1007/978-3-662-46450-2_11] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Opioids are considered the gold standard for the treatment of moderate to severe pain. However, heterogeneity in analgesic efficacy, poor potency and side effects are associated with opioid use, resulting in dose limitations and suboptimal pain management. Traditionally thought to exhibit their analgesic actions via the activation of the neuronal G-protein-coupled opioid receptors, it is now widely accepted that neuronal activity of opioids cannot fully explain the initiation and maintenance of opioid tolerance, hyperalgesia and allodynia. In this review we will highlight the evidence supporting the role of non-neuronal mechanisms in opioid signalling, paying particular attention to the relationship of opioids and immune signalling.
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Affiliation(s)
- Jacob Thomas
- Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia,
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27
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Giri AK, Hruby VJ. Investigational peptide and peptidomimetic μ and δ opioid receptor agonists in the relief of pain. Expert Opin Investig Drugs 2014; 23:227-41. [PMID: 24329035 PMCID: PMC4282681 DOI: 10.1517/13543784.2014.856879] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Current methods for treating prolonged and neuropathic pain are inadequate and lead to toxicities that greatly diminish quality of life. Therefore, new approaches to the treatment of pain states are needed to address these problems. AREAS COVERED The review primarily reviews approaches that have been taken in the peer-reviewed literature of multivalent ligands that interact with both μ and δ opioid receptors as agonists, and in some cases, also with pharmacophores for antagonist ligands that interact with other receptors as antagonists to block pain. EXPERT OPINION Although there are a number of drugs currently on the market for the treatment of pain; none of them are 100% successful. In the authors' opinion, it is clear that new directions and modalities are needed to better address the treatment of prolonged and neuropathic pain; one drug or class clearly is not the answer for all pain therapy. Undoubtedly, there are many different phenotypes of prolonged and neuropathic pain and this should be one avenue to further develop appropriate therapies.
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Affiliation(s)
- Aswini Kumar Giri
- University of Arizona, Department of Chemistry and Biochemistry , 1306 East University Boulevard, PO Box 210041, Tucson, AZ 85721 , USA
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Thomas J, Hutchinson MR. Exploring neuroinflammation as a potential avenue to improve the clinical efficacy of opioids. Expert Rev Neurother 2014; 12:1311-24. [DOI: 10.1586/ern.12.125] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Abstract
Opiates are among the oldest medications available to manage a number of medical problems. Although pain is the current focus, early use initially focused upon the treatment of dysentery. Opium contains high concentrations of both morphine and codeine, along with thebaine, which is used in the synthesis of a number of semisynthetic opioid analgesics. Thus, it is not surprising that new agents were initially based upon the morphine scaffold. The concept of multiple opioid receptors was first suggested almost 50 years ago (Martin, 1967), opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain. Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years. Early pharmacological studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes-primarily through the synthesis of novel agents. These chemical biologic approaches were then eclipsed by the molecular biology revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated.
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Affiliation(s)
- Gavril W Pasternak
- Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065.
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McCleane G. The cholecystokinin antagonist proglumide has an analgesic effect when used alone in human neuropathic pain: a case report. ACTA ACUST UNITED AC 2013. [DOI: 10.1163/156856903321196537] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Díaz-Morán S, Palència M, Mont-Cardona C, Cañete T, Blázquez G, Martínez-Membrives E, López-Aumatell R, Sabariego M, Donaire R, Morón I, Torres C, Martínez-Conejero JA, Tobeña A, Esteban FJ, Fernández-Teruel A. Gene expression in amygdala as a function of differential trait anxiety levels in genetically heterogeneous NIH-HS rats. Behav Brain Res 2013; 252:422-31. [PMID: 23777796 DOI: 10.1016/j.bbr.2013.05.066] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 05/07/2013] [Accepted: 05/10/2013] [Indexed: 12/12/2022]
Abstract
To identify genes involved in anxiety/fear traits, we analyzed the gene expression profile in the amygdala of genetically heterogeneous NIH-HS rats. The NIH-HS rat stock has revealed to be a unique genetic resource for the fine mapping of Quantitative Trait Loci (QTLs) to very small genomic regions, due to the high amount of genetic recombinants accumulated along more than 50 breeding generations, and for the same reason it can be expected that those genetically heterogeneous rats should be especially useful for studying differential gene expression as a function of anxiety-(or other)-related traits. We selected high- and low-anxious NIH-HS rats differing in their number of avoidances in a single 50-trial session of the two-way active avoidance task. Rats were also tested in unconditioned anxiety tests (e.g., elevated zero-maze). Three weeks after behavioural testing, the amygdala was dissected and prepared for the microarray study. There appeared 6 significantly down-regulated and 28 up-regulated genes (fold-change >|2|, FDR<0.05) between the low- and high-anxious groups, with central nervous system-related functions. Regression analyses (stepwise) revealed that differential expression of some genes could be predictive of anxiety/fear responses. Among those genes for which the present results suggest a link with individual differences in trait anxiety, six relevant genes were examined with qRT-PCR, four of which (Ucn3, Tacr3, H2-M9 and Arr3) were validated. Remarkably, some of them are characterized by sharing known functions related with hormonal HPA-axis responses to (and/or modulation of) stress, anxiety or fear, and putative involvement in related neurobehavioural functions. The results confirm the usefulness of NIH-HS rats as a good animal model for research on the neurogenetic basis of anxiety and fear, while suggesting the involvement of some neuropeptide/neuroendocrine pathways on the development of differential anxiety profiles.
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Affiliation(s)
- Sira Díaz-Morán
- Medical Psychology Unit, Department of Psychiatry & Forensic Medicine, Institute of Neurosciences, School of Medicine, Universidad Autónoma de Barcelona, Barcelona, Spain.
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Wen D, Zang G, Sun D, Yang S, Yu F, Li S, Ma C, Cong B. Effects of CCK-8 on the reinstatement of morphine-induced CPP and expression of behavioral sensitization in rats. Neuroscience 2013; 238:230-41. [DOI: 10.1016/j.neuroscience.2013.02.057] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Revised: 02/20/2013] [Accepted: 02/21/2013] [Indexed: 10/27/2022]
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Zhuang Y, Xing JJ, Li J, Zeng BY, Liang FR. History of acupuncture research. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2013; 111:1-23. [PMID: 24215915 DOI: 10.1016/b978-0-12-411545-3.00001-8] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The acupuncture has been practiced in China for more than 3000 years and was spread to Europe and American from the sixteenth to the nineteenth century. The history of acupuncture research was initiated in the eighteenth century and developed rapidly since then. In the past, physicians tried hard to apply acupuncture into clinical practice, while scientists were focused on the possible characteristics of acupoints and meridians. In the modern time, scientists have strived hard to evaluate the real effectiveness of acupuncture and the underlying physiological and biological mechanisms of acupuncture. Reviewing research history from past to present, we are delighted to witness this wonderful development. Accumulated evidences that acupuncture is beneficial in various conditions significantly enhanced our understanding the mechanisms of acupuncture treatment. However, there is still no conclusive evidence in acupuncture clinical studies. The clinical research still needs great improving, while the basic research results need to be appropriately transformed into clinical outcomes. Based on current achievements, we believe that although the challenges and difficulties exist, a more collaborative, innovative, and integrated approach will help us to achieve further progress in future acupuncture research.
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Affiliation(s)
- Yi Zhuang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Effects of exogenous cholecystokinin octapeptide on acquisition of naloxone precipitated withdrawal induced conditioned place aversion in rats. PLoS One 2012; 7:e41860. [PMID: 22848639 PMCID: PMC3407117 DOI: 10.1371/journal.pone.0041860] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Accepted: 06/26/2012] [Indexed: 11/22/2022] Open
Abstract
Cholecystokinin octapeptide (CCK-8), a gut-brain peptide, regulates a variety of physiological behavioral processes. Previously, we reported that exogenous CCK-8 attenuated morphine-induced conditioned place preference, but the possible effects of CCK-8 on aversively motivated drug seeking remained unclear. To investigate the effects of endogenous and exogenous CCK on negative components of morphine withdrawal, we evaluated the effects of CCK receptor antagonists and CCK-8 on the naloxone-precipitated withdrawal-induced conditioned place aversion (CPA). The results showed that CCK2 receptor antagonist (LY-288,513, 10 µg, i.c.v.), but not CCK1 receptor antagonist (L-364,718, 10 µg, i.c.v.), inhibited the acquisition of CPA when given prior to naloxone (0.3 mg/kg) administration in morphine-dependent rats. Similarly, CCK-8 (0.1–1 µg, i.c.v.) significantly attenuated naloxone-precipitated withdrawal-induced CPA, and this inhibitory function was blocked by co-injection with L-364,718. Microinjection of L-364,718, LY-288,513 or CCK-8 to saline pretreated rats produced neither a conditioned preference nor aversion, and the induction of CPA by CCK-8 itself after morphine pretreatments was not significant. Our study identifies a different role of CCK1 and CCK2 receptors in negative affective components of morphine abstinence and an inhibitory effect of exogenous CCK-8 on naloxone-precipitated withdrawal-induced CPA via CCK1 receptor.
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Wen D, Ma CL, Zhang YJ, Meng YX, Ni ZY, Li SJ, Cong B. Cholecystokinin receptor-1 mediates the inhibitory effects of exogenous cholecystokinin octapeptide on cellular morphine dependence. BMC Neurosci 2012; 13:63. [PMID: 22682150 PMCID: PMC3407485 DOI: 10.1186/1471-2202-13-63] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 06/08/2012] [Indexed: 11/16/2022] Open
Abstract
Background Cholecystokinin octapeptide (CCK-8), the most potent endogenous anti-opioid peptide, has been shown to regulate the processes of morphine dependence. In our previous study, we found that exogenous CCK-8 attenuated naloxone induced withdrawal symptoms. To investigate the precise effect of exogenous CCK-8 and the role of cholecystokinin (CCK) 1 and/or 2 receptors in morphine dependence, a SH-SY5Y cell model was employed, in which the μ-opioid receptor, CCK1/2 receptors, and endogenous CCK are co-expressed. Results Forty-eight hours after treating SH-SY5Y cells with morphine (10 μM), naloxone (10 μM) induced a cAMP overshoot, indicating that cellular morphine dependence had been induced. The CCK receptor and endogenous CCK were up-regulated after chronic morphine exposure. The CCK2 receptor antagonist (LY-288,513) at 1–10 μM inhibited the naloxone-precipitated cAMP overshoot, but the CCK1 receptor antagonist (L-364,718) did not. Interestingly, CCK-8 (0.1-1 μM), a strong CCK receptor agonist, dose-dependently inhibited the naloxone-precipitated cAMP overshoot in SH-SY5Y cells when co-pretreated with morphine. The L-364,718 significantly blocked the inhibitory effect of exogenous CCK-8 on the cAMP overshoot at 1–10 μM, while the LY-288,513 did not. Therefore, the CCK2 receptor appears to be necessary for low concentrations of endogenous CCK to potentiate morphine dependence in SH-SY5Y cells. An additional inhibitory effect of CCK-8 at higher concentrations appears to involve the CCK1 receptor. Conclusions This study reveals the difference between exogenous CCK-8 and endogenous CCK effects on the development of morphine dependence, and provides the first evidence for the participation of the CCK1 receptor in the inhibitory effects of exogenous CCK-8 on morphine dependence.
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Affiliation(s)
- Di Wen
- Department of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Shijiazhuang 050017, PR China
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Noble F, Benturquia N, Crete D, Canestrelli C, Mas Nieto M, Wilson J, Roques BP. Relationship between vulnerability to reinforcing effects of morphine and activity of the endogenous cholecystokinin system in Lewis and Fischer rats. Addict Biol 2012; 17:528-38. [PMID: 21309946 DOI: 10.1111/j.1369-1600.2010.00283.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
A great number of studies have shown the presence of physiological interactions between brain neurotransmitter systems in behavioural responses. This is the case for opioid, cholecystokinin (CCK) and dopamine systems. However, so far the role that the CCK system may play in vulnerability to consumption of drugs of abuse is not clear. This was investigated in this study using Lewis rats that are more sensitive to the reinforcing properties of drugs of abuse than Fischer rats. The extraneuronal CCK(8) levels and brain CCK(2) receptors were found higher in Fischer than in Lewis rats in the nucleus accumbens, one of the most important structures involved in drug consumption. Moreover, pharmacological modulation of the CCK system by administration of a selective CCK(2) agonist blocked, in the conditioned place preference, the reinforcing effects of morphine in Lewis rats, whereas a selective CCK(2) antagonist revealed reinforcing effects of the alkaloid in Fischer rats. These results obtained following systemic administrations of the CCK ligands were confirmed following microinjection into the nucleus accumbens. Thus, a low level of CCK efflux in the nucleus accumbens could be one of the many factors involved in drug reinforcing effects, whereas a high level of CCK efflux could attenuate it.
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Affiliation(s)
- Florence Noble
- Université Paris Descartes, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, France.
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Wen D, Cong B, Ma C, Yang S, Yu H, Ni Z, Li S. The effects of exogenous CCK-8 on the acquisition and expression of morphine-induced CPP. Neurosci Lett 2012; 510:24-8. [PMID: 22245440 DOI: 10.1016/j.neulet.2011.12.063] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Revised: 11/17/2011] [Accepted: 12/29/2011] [Indexed: 11/27/2022]
Abstract
Cholecystokinin octapeptide (CCK-8) is the most potent endogenous anti-opioid peptide and regulates a variety of physiological processes. In our previous study, we found that exogenous CCK-8 attenuated naloxone-induced withdrawal symptoms, but the possible regulative effects of CCK-8 on the rewarding effects of morphine were not examined. In the present study, we aimed to determine the exact effects of exogenous CCK-8 at various doses on the rewarding action of morphine by utilizing the unbiased conditioned place preference (CPP) paradigm. We therefore examined the effects of CCK-8 on the acquisition, expression and extinction of morphine-induced CPP and on locomotor activity. The results showed that CCK-8 (0.01-1μg, i.c.v.), administered alone, induced neither CPP nor place aversion, but blocked the acquisition of CPP when administered with 10mg/kg morphine. The highest dose of CCK-8 (1μg) administered before CPP testing increased CPP and, along with lower doses (0.1μg), reduced its extinction. In addition, the highest dose (1μg) of CCK-8 suppressed locomotor activity. Our study provides the first behavioral evidence for the inhibitory effects of exogenous CCK-8 on rewarding activity and reveals significant effects of exogenous CCK-8 on various stages of place preference and the development of opioid dependence.
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Affiliation(s)
- Di Wen
- Department of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Shijiazhuang 050017, PR China
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Marini P, Romanelli L, Valeri D, Cascio MG, Tucci P, Valeri P, Palmery M. Biphasic regulation of the acute μ-withdrawal and CCk-8 contracture responses by the ORL-1 system in guinea pig ileum. Pharmacol Res 2012; 65:100-10. [PMID: 21875667 DOI: 10.1016/j.phrs.2011.08.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2011] [Revised: 07/26/2011] [Accepted: 08/12/2011] [Indexed: 10/17/2022]
Abstract
The cloning of the opioid-receptor-like receptor (ORL-1) and the identification of the orphaninFQ/nociceptin (OFQ/N) as its endogenous agonist has revealed a new G-protein-coupled receptor signalling system. The structural and functional homology of ORL-1 to the opioid receptor systems has posed a number of challenges in the understanding the often competing physiological responses elicited by these G-protein-coupled receptors. We had previously shown that in guinea pig ileum (GPI), the acute μ-withdrawal response is under the inhibitory control of several systems. Specifically, we found that the exposure to a μ-opioid receptor agonist activates indirectly the κ-opioid, the A(1)-adenosine and the cannabinoid CB(1) systems, that in turn inhibit the withdrawal response. The indirect activation of these systems is prevented by the peptide cholecystokinin-8 (CCk-8). In the present study, we have investigated whether the ORL-1 system is also involved in the regulation of the acute μ-withdrawal response. Interestingly, we found that in GPI preparation, the ORL-1 system is not indirectly activated by the μ-opioid receptor stimulation, but instead the system is able by itself to directly regulate the acute μ-withdrawal response. Moreover, we have demonstrated that the ORL-1 system behaves both as anti-opioid or opioid-like system based on the level of activation. The same behaviour has also been observed in presence of CCk-8. Furthermore, in GPI, the existence of an endogenous tone of the ORL-1 system has been demonstrated. We concluded that the ORL-1 system acts as a neuromodulatory system, whose action is strictly related to the modulation of excitatory neurotrasmitters released in GPI enteric nervous system.
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Affiliation(s)
- Pietro Marini
- School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
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Marshall TM, Herman DS, Largent-Milnes TM, Badghisi H, Zuber K, Holt SC, Lai J, Porreca F, Vanderah TW. Activation of descending pain-facilitatory pathways from the rostral ventromedial medulla by cholecystokinin elicits release of prostaglandin-E₂ in the spinal cord. Pain 2011; 153:86-94. [PMID: 22030324 DOI: 10.1016/j.pain.2011.09.021] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Revised: 09/20/2011] [Accepted: 09/21/2011] [Indexed: 11/18/2022]
Abstract
Cholecystokinin (CCK) has been suggested to be both pro-nociceptive and "anti-opioid" by actions on pain-modulatory cells within the rostral ventromedial medulla (RVM). One consequence of activation of RVM CCK₂ receptors may be enhanced spinal nociceptive transmission; but how this might occur, especially in states of pathological pain, is unknown. Here, in vivo microdialysis was used to demonstrate that levels of RVM CCK increased by approximately 2-fold after ligation of L₅/L₆ spinal nerves (SNL). Microinjection of CCK into the RVM of naïve rats elicited hypersensitivity to tactile stimulation of the hindpaw. In addition, RVM CCK elicited a time-related increase in (prostaglandin-E₂) PGE₂ measured in cerebrospinal fluid from the lumbar spinal cord. The peak increase in spinal PGE₂ was approximately 5-fold and was observed at approximately 80 minutes post-RVM CCK, a time coincident with maximal RVM CCK-induced mechanical hypersensitivity. Spinal administration of naproxen, a nonselective COX-inhibitor, significantly attenuated RVM CCK-induced hindpaw tactile hypersensitivity. RVM-CCK also resulted in a 2-fold increase in spinal 5-hydroxyindoleacetic acid (5-HIAA), a 5-hydoxytryptophan (5-HT) metabolite, as compared with controls, and mechanical hypersensitivity that was attenuated by spinal application of ondansetron, a 5-HT₃ antagonist. The present studies suggest that chronic nerve injury can result in activation of descending facilitatory mechanisms that may promote hyperalgesia via ultimate release of PGE₂ and 5-HT in the spinal cord.
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Affiliation(s)
- Timothy M Marshall
- Department of Pharmacology, University of Arizona Health Sciences Center, College of Medicine, Tucson, AZ, USA
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Proglumide enhances the antinociceptive effect of cyclooxygenase inhibitors in diabetic rats in the formalin test. Eur J Pharmacol 2011; 664:8-13. [DOI: 10.1016/j.ejphar.2011.04.044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Revised: 03/25/2011] [Accepted: 04/14/2011] [Indexed: 01/30/2023]
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Mitchell VA, Jeong HJ, Drew GM, Vaughan CW. Cholecystokinin exerts an effect via the endocannabinoid system to inhibit GABAergic transmission in midbrain periaqueductal gray. Neuropsychopharmacology 2011; 36:1801-10. [PMID: 21525858 PMCID: PMC3154098 DOI: 10.1038/npp.2011.59] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cholecystokinin modulates pain and anxiety via its functions within brain regions such as the midbrain periaqueductal gray (PAG). The aim of this study was to examine the cellular actions of cholecystokinin on PAG neurons. Whole-cell patch clamp recordings were made from rat midbrain PAG slices in vitro to examine the postsynaptic effects of cholecystokinin and its effects on synaptic transmission. Sulfated cholecystokinin-(26-33) (CCK-S, 100-300 nM), but not non-sulfated cholecystokinin-(26-33) (CCK-NS, 100-300 nM) produced an inward current in a sub-population of opioid sensitive and insensitive PAG neurons, which did not reverse over a range of membrane potentials. The CCK-S-induced current was abolished by the CCK1 selective antagonist devazepide (100 nM), but not by the CCK2 selective antagonists CI988 (100 nM, 1 μM) and LY225910 (1 μM). CCK-S, but not CCK-NS produced a reduction in the amplitude of evoked GABA(A)-mediated inhibitory postsynaptic currents (IPSCs) and an increase in the evoked IPSC paired-pulse ratio. By contrast, CCK-S had little effect on the rate and amplitude of TTX-resistant miniature IPSCs under basal conditions and when external K(+) was elevated. The CCK-S-induced inhibition of evoked IPSCs was abolished by the cannabinoid CB1 receptor antagonist AM251 (3 μM), the mGluR5 antagonist MPEP (10 μM) and the 1, 2-diacylglycerol lipase (DAGLα) inhibitor tetrahydrolipstatin (10 μM). In addition, CCK-S produced an increase in the rate of spontaneous non-NMDA-mediated, TTX-dependent excitatory postsynaptic currents (EPSCs). These results suggest that cholecystokinin produces direct neuronal depolarisation via CCK1 receptors and inhibits GABAergic synaptic transmission via action potential-dependent release of glutamate and mGluR5-induced endocannabinoid signaling. Thus, cholecystokinin has cellular actions within the PAG that can both oppose and reinforce opioid and cannabinoid modulation of pain and anxiety within this brain structure.
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Affiliation(s)
- Vanessa A Mitchell
- Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney at Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Hyo-Jin Jeong
- Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney at Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Geoffrey M Drew
- Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney at Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Christopher W Vaughan
- Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney at Royal North Shore Hospital, St Leonards, NSW, Australia,Pain Management Research Institute, Level 13, Kolling Building, Kolling Institute for Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia, Tel: +61 29 926 4950, Fax: +61 29 926 7659, E-mail: , http://www.pmri.med.usyd.edu.au
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Abstract
Twin and triplet drugs are defined as compounds that contain respectively two and three pharmacophore components exerting pharmacological effects in a molecule. The twin drug bearing the same pharmacophores is a "symmetrical twin drug", whereas that possessing different pharmacophores is a "nonsymmetrical twin drug." In general, the symmetrical twin drug is expected to produce more potent and/or selective pharmacological effects, whereas the nonsymmetrical twin drug is anticipated to show both pharmacological activities stemming from the individual pharmacophores (dual action). On the other hand, nonsymmetrical triplet drugs, which have two of the same pharmacophores and one different moiety, are expected to elicit both increased pharmacological action and dual action. The two identical portions could bind the same receptor sites simultaneously while the third portion could bind a different receptor site or enzyme. This review will mainly focus on the twin and triplet drugs with an evaluation of their in vivo pharmacological effects, and will also include a description of their pharmacology and synthesis.
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Affiliation(s)
- Hideaki Fujii
- School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
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Yamada Y, Ohinata K, Lipkowski AW, Yoshikawa M. Rapakinin, Arg-Ile-Tyr, derived from rapeseed napin, shows anti-opioid activity via the prostaglandin IP receptor followed by the cholecystokinin CCK(2) receptor in mice. Peptides 2011; 32:281-5. [PMID: 21129424 DOI: 10.1016/j.peptides.2010.11.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2010] [Revised: 11/17/2010] [Accepted: 11/17/2010] [Indexed: 12/30/2022]
Abstract
Rapakinin, Arg-Ile-Tyr, is a vasorelaxing, anti-hypertensive and anorexigenic peptide derived from rapeseed napin. In this study, we found that rapakinin intracerebroventricularly administered to mice inhibited the analgesic effect of morphine, evaluated by the tail-pinch test. The anti-opioid activity of rapakinin was blocked by LY225910, an antagonist of the cholecystokinin (CCK) CCK(2) receptor, but not by lorglumide, an antagonist of the CCK(1) receptor. The anti-opioid activity of rapakinin was also blocked by CAY10441, an antagonist of the prostaglandin (PG) IP receptor. These results suggest that the anti-opioid activity of rapakinin is mediated by the CCK(2) and IP receptors. The anti-opioid activity induced by ciprostene, an IP receptor agonist, was blocked by LY225910, while that of CCK-8 was not blocked by CAY10441. Thus, it is demonstrated that the CCK-CCK(2) system was activated downstream of the PGI(2)-IP receptor system. Taken together, rapakinin shows anti-opioid activity via the activation of the PGI(2)-IP receptor system followed by the CCK-CCK(2) receptor system.
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Affiliation(s)
- Yuko Yamada
- Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
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Shi TF, Yang CX, Yang DX, Gao HR, Zhang GW, Zhang D, Jiao RS, Xu MY, Qiao HQ. L-364,718 potentiates electroacupuncture analgesia through cck-a receptor of pain-related neurons in the nucleus parafascicularis. Neurochem Res 2010; 36:129-38. [PMID: 20953702 DOI: 10.1007/s11064-010-0281-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2010] [Indexed: 12/31/2022]
Abstract
Electroacupuncture (EA) has been successfully used to alleviate pain produced by various noxious stimulus. Cholecystokinin-8 (CCK-8) is a neuropeptide involved in the mediation of pain. We have previously shown that CCK-8 could antagonize the analgesic effects of EA on pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the nucleus parafascicularis (nPf). However, its mechanism of action is not clear. In the present study, we applied behavioral and neuroelectrophysiological methods to determine whether the mechanisms of CCK-8 antagonism to EA analgesia are mediated through the CCK-A receptors of PENs and PINs in the nPf of rats. We found that focusing radiant heat on the tail of rats caused a simultaneous increase in the evoked discharge of PENs or a decrease in the evoked discharge of PINs in the nPf and the tail-flick reflex. This showed that radiant heat could induce pain. EA stimulation at the bilateral ST 36 acupoints in rats for 15 min resulted in an inhibition of the electrical activity of PEN, potentiation of the electrical activity of PIN, and prolongation in tail-flick latency (TFL), i.e. EA stimulation produced an analgesic effect. The analgesic effect of EA was antagonized when CCK-8 was injected into the intracerebral ventricle of rats. The antagonistic effect of CCK-8 on EA analgesia was reversed by an injection of CCK-A receptor antagonist L-364,718 (100 ng/μl) into the nPf of rats. Our results suggest that the pain-related neurons in the nPf have an important role in mediating EA analgesia. L-364,718 potentiates EA analgesia through the CCK-A receptor of PENs and PINs in the nPf.
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Affiliation(s)
- T F Shi
- Department of Surgery of Second Affiliated Hospital, Harbin Medical University, 150081 Harbin, Heilongjiang, People's Republic of China
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Lee YS, Fernandes S, Kulkarani V, Mayorov A, Davis P, Ma SW, Brown K, Gillies RJ, Lai J, Porreca F, Hruby VJ. Design and synthesis of trivalent ligands targeting opioid, cholecystokinin, and melanocortin receptors for the treatment of pain. Bioorg Med Chem Lett 2010; 20:4080-4. [PMID: 20547453 DOI: 10.1016/j.bmcl.2010.05.078] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Revised: 05/18/2010] [Accepted: 05/19/2010] [Indexed: 11/29/2022]
Abstract
It has been known that co-administration of morphine with either cholecystokinin (CCK) receptor or melanocortin (MC) receptor antagonists enhance morphine's analgesic efficacy by reducing serious side effects such as tolerance and addiction. Considering these synergistic effects, we have designed trivalent ligands in which all three different pharmacophores for opioid, CCK, and MC receptors are combined in such a way as to conserve their own topographical pharmacophore structures. These ligands, excluding the cyclic compound, were synthesized by solid phase synthesis using Rink-amide resin under microwave assistance in very high yields. These trivalent ligands bind to their respective receptors well demonstrating that the topographical pharmacophore structures for the three receptors were retained for receptor binding. Ligand 10 was a lead compound to show the best biological activities at all three receptors.
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Affiliation(s)
- Yeon Sun Lee
- Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA
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Harikumar KG, Akgün E, Portoghese PS, Miller LJ. Modulation of cell surface expression of nonactivated cholecystokinin receptors using bivalent ligand-induced internalization. J Med Chem 2010; 53:2836-42. [PMID: 20235611 DOI: 10.1021/jm100135g] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
CCK(2) receptor antagonists potentiate pain relief by MOP receptor agonists. In an attempt to enhance this effect, we prepared bivalent ligands incorporating CCK(2) receptor antagonist and MOP receptor agonist pharmacophores. (9) Ligands with 16- to 22-atom spacers could simultaneously bind both receptors but provided no advantage in activity over individual ligands. We now examine the effect of these ligands on receptor internalization as a mechanism of receptor regulation. We prepared CHO cell lines expressing nonfluorescent halves (YN and YC) of yellow fluorescent protein attached to each receptor. Spatial approximation of constructs was needed to yield fluorescence. Monovalent MOP agonist 1 signaled normally and internalized the MOP receptor. Monovalent CCK(2) antagonist 2 did not stimulate receptor internalization. In the dual receptor-bearing cells, bivalent ligands 3a-c capable of simultaneously binding both receptors resulted in cell surface fluorescence and internalization of the fluorescent complex in a time- and temperature-dependent manner. Bivalent ligand 4 with spacer too short to occupy both receptors simultaneously yielded no signal. Receptor tethering with appropriate bivalent ligands can down-regulate signaling by moving a nonactivated receptor into the endocytic pathway.
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Affiliation(s)
- Kaleeckal G Harikumar
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA
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Kornetsky C, Knapp CM, Tozier L, Pak A. Medial forebrain stimulation enhances intracranial nociception and attenuates morphine analgesia suggesting the existence of an endogenous opioid antagonist. Pharmacol Biochem Behav 2010; 95:273-7. [PMID: 20149816 PMCID: PMC2859829 DOI: 10.1016/j.pbb.2010.01.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2009] [Revised: 01/25/2010] [Accepted: 01/30/2010] [Indexed: 11/16/2022]
Abstract
The purpose of this experiment was to test in the rat the hypotheses that activation of the brain reward system would attenuate the effects of intracranial nociceptive stimulation and would potentiate the antinociceptive effects of morphine. In this experiment pain (nociception) was generated by electrical stimulation of a brain pain pathway, the mesencephalic reticular formation (MRF) of the rat. Reward pathway stimulation was to the medial forebrain bundle at the level of the lateral hypothalamus (MFB-LH). Current thresholds for escape from MRF stimulation were determined using a modification of the psychophysical methods of limits. MRF stimulation was delivered concurrently with different intensities of non-contingent MFB-LH stimulation. The effects of morphine and saline were determined under all stimulation conditions. Contrary to expectation MFB-LH stimulation significantly lowered MRF stimulation escape thresholds. Morphine administration elevated MRF thresholds in the absence of MFB-LH stimulation. However, this effect was blocked by concurrent MFB-LH stimulation. These findings, which mimic the effects of the opiate antagonist naloxone, i.e., potentiating of pain and antagonism of morphine's analgesic effects, suggest the presence of an endogenous opiate receptor antagonist.
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Affiliation(s)
- Conan Kornetsky
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, United States.
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Cholecystokinin receptors mediate tolerance to the analgesic effect of TENS in arthritic rats. Pain 2009; 148:84-93. [PMID: 19944533 DOI: 10.1016/j.pain.2009.10.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2009] [Revised: 09/25/2009] [Accepted: 10/15/2009] [Indexed: 11/21/2022]
Abstract
Transcutaneous electrical nerve stimulation (TENS) is a treatment for pain that involves placement of electrical stimulation through the skin for pain relief. Previous work from our laboratory shows that repeated application of TENS produces analgesic tolerance by the fourth day and a concomitant cross-tolerance at spinal opioid receptors. Prior pharmacological studies show that blockade of cholecystokinin (CCK) receptors systemically and spinally prevents the development of analgesic tolerance to repeated doses of opioid agonists. We therefore hypothesized that systemic and intrathecal blockade of CCK receptors would prevent the development of analgesic tolerance to TENS, and cross-tolerance at spinal opioid receptors. In animals with knee joint inflammation (3% kaolin/carrageenan), high (100Hz) or low frequency (4Hz) TENS was applied daily and the mechanical withdrawal thresholds of the muscle and paw were examined. We tested thresholds before and after inflammation, and before and after TENS. Animals treated systemically, prior to TENS, with the CCK antagonist, proglumide, did not develop tolerance to repeated application of TENS on the fourth day. Spinal blockade of CCK-A or CCK-B receptors blocked the development of tolerance to high and low frequency TENS, respectively. In the same animals we show that spinal blockade of CCK-A receptors prevents cross-tolerance at spinal delta-opioid receptors that normally occurs with high frequency TENS; and blockade of CCK-B receptors prevents cross-tolerance at spinal mu-opioid receptors that normally occurs with low frequency TENS. Thus, we conclude that blockade of CCK receptors prevents the development of analgesic tolerance to repeated application of TENS in a frequency-dependent manner.
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Yang CX, Shi TF, Liang QC, Yang BF, Jiao RS, Zhang H, Zhang Y, Xu MY. Cholecystokinin-8 antagonizes electroacupuncture analgesia through its B receptor in the caudate nucleus. Neuromodulation 2009; 13:93-8. [PMID: 21992780 DOI: 10.1111/j.1525-1403.2009.00247.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES The analgesic effect of electroacupuncture (EA) stimulation has been proved. However, its mechanism of action is not clear. It has been well-known that cholecystokinin-8 (CCK-8) is a neuropeptide which is mainly related to the mediation of pain. The caudate nucleus was selected to determine if the release of CCK and the neural activity in this nucleus were involved in producing EA analgesia. MATERIALS AND METHODS Radiant heat focused on the rat-tail was used as the noxious stimulus. The pain threshold of rats was measured by tail-flick latency (TFL). EA stimulation at the bilateral Zusanli (ST 36) acupoints of rats was used to investigate the effects of EA analgesia. The electrical activities of pain-excited neurons (PEN) and pain-inhibited neurons (PIN) in the caudate nucleus were recorded with a glass microelectrode. The present study examined the antagonistic effects of the intracerebral ventricular injection of CCK-8 on EA analgesia and reversing effects of CCK-B receptor antagonist (L-365,260) injection into the caudate nucleus on CCK-8. RESULTS The radiant heat focused on the tail of rats caused an increase in the evoked discharge of PEN and a reduction in the evoked discharge of PIN. EA stimulation at the bilateral ST 36 acupoints of rats resulted in the inhibition of PEN, the potentiation of PIN, and prolongation of TFL. The analgesic effect of EA was antagonized when CCK-8 was injected into the intracerebral ventricle of rats. The antagonistic effect of CCK-8 on EA analgesia was reversed by injection of CCK-B receptor antagonist (L-365,260) into the caudate nucleus of rats. CONCLUSIONS Our results suggest that CCK-8 antagonize EA analgesia through its B receptor.
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Affiliation(s)
- Chun-Xiao Yang
- Department of Neurology of 2nd Affiliated Hospital, Harbin, Heilongjiang Province, China; College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China; and Laboratory of Neural Electrophysiology, Department of Physiology, Harbin Medical University, Harbin, Heilongjiang Province, China
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