title: Antihyperalgesic effects of the muscarinic receptor ligand vedaclidine in models involving central sensitization in rats.
abstract: It is well established that muscarinic cholinergic agonists produce antinociceptive effects in a number of acute pain models. However, relatively little is known about the effects of muscarinic receptor agonists in models which involve central sensitization in pain pathways. The purpose of the present studies was to evaluate the effects of vedaclidine, a muscarinic receptor mixed agonist/antagonist across receptor subtypes, in models involving central sensitization. Vedaclidine (0.3-10 mg/kg s.c.) produced dose-related antihyperalgesic effects in the formalin test as well as a dose-related reversal of capsaicin-induced mechanical hyperalgesia in rats. In the carrageenan test, vedaclidine (0.1-30 mg/kg) produced a dose-related reversal of both mechanical and thermal hyperalgesia that were antagonized by the muscarinic receptor antagonist scopolamine. In addition, the antihyperalgesic effects of vedaclidine in the carrageenan test were synergistic with the antihyperalgesic effects of the non-steroidal antiinflammatory drug ketoprofen, as demonstrated by isobolographic analysis. The present studies demonstrate that vedaclidine produces antihyperalgesic effects in models involving central sensitization, suggesting that vedaclidine, and potentially other muscarinic receptor agonists, may have clinical utility in the management of pain states involving central sensitization, such as neuropathic and inflammatory pain states.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Harlan E
authors.initials: HE
authors.lastname: Shannon
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Dominic L
authors.initials: DL
authors.lastname: Li
authors.forename: Steven C
authors.initials: SC
authors.lastname: Peters
authors.forename: Rosa M A
authors.initials: RMA
authors.lastname: Simmons
authors.forename: Smriti
authors.initials: S
authors.lastname: Iyengar
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy*; D007660:Ketoprofen / Q000494:pharmacology; D008024:Ligands; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology* / Q000627:therapeutic use*; D010147:Pain Measurement / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000502:physiology*; D013830:Thiadiazoles / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008024:Ligands; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; D007660:Ketoprofen; C101714:LY 297802