Systemic pre‐treatment with a group II mGlu agonist, LY379268, reduces hyperalgesia in vivo

Previous studies investigating the role of metabotropic glutamate (mGlu) receptors in nociceptive processing have been hampered by the lack of systemically active, selective, ligands. This study investigates the possible analgesic and/or anti‐hyperalgesic properties of the most potent compound to date that has systemic agonist activity at group II mGlu receptors, LY379268. In testing the drug in rats as an analgesic to acute noxious stimuli, LY379268 (in doses up to 3 mg kg −1 i.p.) did not affect withdrawal latencies to either mechanical or thermal stimulation. However, when a 3 mg kg −1 dose was given prior to an intraplantar injection of carrageenan, the inflammatory hyperalgesia that developed was significantly delayed compared to saline pre‐treated controls, without affecting the inflammation of the paw. A similar dose of the mGlu‐inactive enantiomer, LY379267, was not anti‐hyperalgesic. In a model of mouse tail withdrawal to warm water, LY379268 (12 mg kg −1 i.p.), given before a subcutaneous tail injection of capsaicin, reduced the subsequent neurogenic hyperalgesia. Rota‐rod testing showed that the drug did not produce a motor impairment in rats at antihyperalgesic doses. The results indicate that systemic activation of this group of mGlu receptors reduces both inflammatory and neurogenic thermal hyperalgesia.British Journal of Pharmacology (2002) 135 , 1255–1262; doi: 10.1038/sj.bjp.0704583