Selective agonist of group II glutamate metabotropic receptors, LY354740, inhibits tolerance to analgesic effects of morphine in mice

1 Antagonists of glutamate N-methyl-D-aspartate (NMDA) subtype receptor inh ibit the development of tolerance to the antinociceptive effects of opioids . Another way to inhibit the function of glutamate receptors is the stimula tion of presynaptic metabotropic group II (mGluRII) receptors. Because LY35 4740 ((+)-2-aminobicyclo [3,1,0] hexane-2,6-dicarboxylic acid) is the first systemically active agonist of group II mGlu receptors, we investigated if this compound might inhibit the development of tolerance to antinociceptiv e effects of morphine and fentanyl. 2 As assessed by cumulative dose-response approach in the tail-flick test, administration of 10 mg kg(-1) morphine bid s.c. to male Albino Swiss mice for 6 days, right-shifted morphine dose-response curve by similar to 4 fold . In a separate group of mice, 12 injections of 0.04 mg kg(-1) of fentanyl over 3 days, right-shifted fentanyl dose-response curve by similar to 3.3 f old. 3 In experiment 1, LY354740 (1 and 10, but not 0.1 mg kg(-1)) as well as th e reference compound, an uncompetitive NMDA receptor antagonist memantine ( 7.5 mg kg(-1)) inhibited the development of morphine tolerance. Neither LY3 54740 (10 mg kg(-1)) nor memantine (7.5 mg kg(-1)) affected the development of tolerance to fentanyl. In experiment 2, neither LY354740 (1 and 10 mg k g(-1)) nor memantine (7.5 mg kg(-1)) affected the tail-flick antinociceptiv e response, or the acute antinociceptive effect of morphine. 4 The present results are the first to suggest that the development of anti nociceptive morphine tolerance may be inhibited by metabotropic group II gl utamate agonist.