The M1/M4 preferring agonist xanomeline is analgesic in rodent models of chronic inflammatory and neuropathic pain via central site of action
| Autor: | Martin Coupal, Nektaria Markoglou, Fraser McIntosh, Carole Puma, Jennifer M. A. Laird, Xiao Hong Yu, Martin N. Perkins, Giovanni Martino, Annie-Kim Gilbert |
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| Rok vydání: | 2011 |
| Předmět: |
Central Nervous System
Male Agonist Pyridines medicine.drug_class Analgesic CHO Cells Muscarinic Agonists Pharmacology Muscarinic agonist Rats Sprague-Dawley Mice chemistry.chemical_compound Cricetulus Cricetinae Thiadiazoles Muscarinic acetylcholine receptor Animals Medicine Analgesics Receptor Muscarinic M4 business.industry Receptor Muscarinic M1 Chronic pain Muscarinic acetylcholine receptor M1 medicine.disease Pirenzepine Rats Mice Inbred C57BL Disease Models Animal Anesthesiology and Pain Medicine Neurology chemistry Neuralgia Neurology (clinical) Chronic Pain business Xanomeline medicine.drug |
| Zdroj: | Pain. 152:2852-2860 |
| ISSN: | 0304-3959 |
| Popis: | The role of muscarinic receptor subtype-1 (M1) in chronic pain is unclear. In an attempt to gain an understanding of its role, we have tested xanomeline, an M1/M4-preferring agonist, together with nonselective (scopolamine and pirenzepine), and selective (MT-7 and MT-3) muscarinic receptor (M1 and M4, respectively) antagonists in a number of inflammatory and neuropathic pain models. Xanomeline potently and effectively reversed tactile allodynia and heat hyperalgesia associated with established neuropathic and inflammatory pain in both rat and mouse models. Scopolamine and pirenzepine completely blocked the analgesic response to xanomeline, confirming that the analgesic effect is mediated by the muscarinic system. The highly selective M1 receptor toxin, MT-7, almost completely abolished the analgesic response to xanomeline when administered supraspinally. However, the highly selective M4 receptor toxin, MT-3, only marginally reversed the analgesia when given supraspinally, and had no effect when given spinally. In conclusion, the data presented show that the nonselective muscarinic agonist xanomeline is analgesic in models of persistent pain and suggest that the activation of supraspinal M1 receptors, and to a lesser extent supraspinal M4 receptors, contributes to that analgesia. |
| Databáze: | OpenAIRE |
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