The M1/M4 preferring agonist xanomeline is analgesic in rodent models of chronic inflammatory and neuropathic pain via central site of action.
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.
AstraZeneca R&D Montreal, St-Laurent, QC, Canada Department of Pharmacology and Experimental Therapeutics, McGill University, Montreal, Canada Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
Giovanni
G
Martino
Carole
C
Puma
Xiao Hong
XH
Yu
Annie-Kim
AK
Gilbert
Martin
M
Coupal
Nektaria
N
Markoglou
Fraser S
FS
McIntosh
Martin N
MN
Perkins
Jennifer M A
JMA
Laird
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059350:Chronic Pain / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D043588:Receptor, Muscarinic M4 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology*
D000700:Analgesics; D018721:Muscarinic Agonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4; D013830:Thiadiazoles; C075257:xanomeline