The selective metabotropic glutamate receptor 7 allosteric agonist AMN082 inhibits inflammatory pain-induced and incision-induced hypersensitivity in rat.
This study characterized the contribution of metabotropic glutamate receptor 7 (mGlu7 receptor) activation to the development of inflammatory hyperalgesia and allodynia, using a novel, systemically active mGlu7 receptor allosteric agonist, N, N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082). The effects of AMN082 (0.1, 1 or 5 mg/kg, intraperitoneally; 5 or 50 nmol, intrathecally) or diclofenac (5 mg/kg, intraperitoneally) administered 30 min preprocedure or 3 h postprocedure on hindpaw withdrawal latency (in seconds) to thermal stimulation, and response threshold (in grams) to mechanical stimulation, were measured in adult rats (n = 6-8 per group) before and up to 24 h after intradermal injection of carrageenan into the hindpaw or hindpaw incision. Precarrageenan injection of 1 and 5 mg/kg AMN082, but not diclofenac inhibited thermal hyperalgesia, whereas postcarrageenan, both AMN082 and diclofenac attenuated thermal hyperalgesia and allodynia. In the paw incision model, presurgical and postsurgical administration of 1 and 5 mg/kg AMN082 inhibited thermal hyperalgesia, but not allodynia, whereas diclofenac was effective in attenuating both thermal hyperalgesia and allodynia but only when administered postsurgically. Intrathecal injection of AMN082 postcarrageenan and postsurgery also significantly attenuated thermal hyperalgesia. Enhancing endogenous mGlu7 receptor activity inhibits postinjury stimulus-evoked hypersensitivity and may be of therapeutic benefit for the treatment of inflammatory and incision-induced pain.
Dolan
Sharron
S
Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK. sharron.dolan@gcal.ac.uk
Gunn
Mark D
MD
Biddlestone
Laura
L
Nolan
Andrea M
AM
D000494:Allosteric Regulation; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D002351:Carrageenan; D004008:Diclofenac / Q000627:therapeutic use; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D007271:Injections, Intradermal; D007278:Injections, Spinal; D008297:Male; D010146:Pain / Q000188:drug therapy*; D010149:Postoperative Pain / Q000188:drug therapy*; D010768:Phosphoserine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001559:Benzhydryl Compounds; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; C120877:methylserine phosphate; D004008:Diclofenac; D010768:Phosphoserine; D002351:Carrageenan