The M1/M4 preferring agonist xanomeline is analgesic in rodent models of chronic inflammatory and neuropathic pain via central site of action

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. The role of muscarinic receptor subtype-1...

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Bibliographic Details
Published in:	Pain (Amsterdam) Vol. 152; no. 12; pp. 2852 - 2860
Main Authors:	Martino, Giovanni, Puma, Carole, Yu, Xiao Hong, Gilbert, Annie-Kim, Coupal, Martin, Markoglou, Nektaria, McIntosh, Fraser S., Perkins, Martin N., Laird, Jennifer M.A.
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA Elsevier B.V 01-12-2011 Lippincott Williams & Wilkins, Inc Elsevier
Subjects:	Analgesics Analgesics - pharmacology Animals Biological and medical sciences Central Nervous System - drug effects Central Nervous System - metabolism Central Nervous System - pathology CHO Cells Chronic Pain - drug therapy Chronic Pain - metabolism Chronic Pain - pathology Cricetinae Disease Models, Animal Inflammatory Male Medical sciences Mice Mice, Inbred C57BL MT-3 MT-7 Muscarinic Agonists - pharmacology Nervous system (semeiology, syndromes) Nervous system as a whole Neuralgia - drug therapy Neuralgia - metabolism Neuralgia - pathology Neurology Neuropathic Neuropharmacology Pharmacology. Drug treatments Pyridines - pharmacology Rats Rats, Sprague-Dawley Receptor, Muscarinic M1 - agonists Receptor, Muscarinic M1 - genetics Receptor, Muscarinic M1 - metabolism Receptor, Muscarinic M4 - agonists Receptor, Muscarinic M4 - genetics Receptor, Muscarinic M4 - metabolism Supraspinal Thiadiazoles - pharmacology Xanomeline Supraspinal Inflammatory MT-3 Xanomeline MT-7 Neuropathic Allodynia Animal model Rodentia Site of action Hyperalgesia M1 Muscarinic receptor Toxin Cholinergic receptor Vertebrata Mammalia Analgesic Pain M4 muscarinic receptor Subtype Biological receptor
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Summary:	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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0304-3959 1872-6623
DOI:	10.1016/j.pain.2011.09.017