Morphine in Combination with Metabotropic Glutamate Receptor Antagonists on Schedule-Controlled Responding and Thermal Nociception

Abstract

The present study examined the interactive effects of morphine in combination with metabotropic glutamate (mGlu) receptor antagonists on schedule-controlled responding and thermal nociception. Drug interaction data were examined with isobolographic and dose-addition analysis. Morphine, the mGlu1 receptor antagonist JNJ16259685 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone], the mGlu5 receptor antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride], and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] all decreased rates of schedule-controlled responding. JNJ16259685/morphine, MPEP/morphine, and LY341495/morphine mixtures produced additive effects on this endpoint. Morphine also produced dose-dependent antinociception in the assay of thermal nociception, whereas JNJ16259685, MPEP, and LY341495 failed to produce an effect. In this assay, JNJ16259685 and LY341495 potentiated the antinociceptive effects of morphine, whereas MPEP/morphine mixtures produced additive effects. These results suggest that an mGlu1 and an mGlu2/3 receptor antagonist, but not an mGlu5 receptor antagonist, selectively enhance the antinociceptive effects of morphine. In addition, these data confirm that the behavioral effects of drug mixtures depend on the endpoint under study.Glutamatergic neurotransmission works by activating both ionotropic glutamate (iGlu) and G-protein-coupled metabotropic glutamate (mGlu) receptor subtypes and is thought to play a modulatory role in the behavioral effects of morphine. To date, the most thoroughly investigated system of the glutamate receptor subtypes is the ionotropic N-methyl-D-aspartate (NMDA) receptor. Several lines of evidence suggest that pharmacological antagonism of the NMDA receptor blocks morphine-induced conditioned place preference (Papp et al

Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation

“…Group II mGluR antagonists (15,16,45) enhance the inhibitory effect of opioid receptor agonists on somatic nociceptive responses induced by thermal stimuli or formalin injection. On the other hand, a group II mGluR agonist also enhances the opioid-induced antinociceptive effect on neuropathic pain (29).…”

“…antinociception (15,16,29,45). Opioid-induced antinociceptive effects were enhanced by antagonists (15,16,45) and agonists (29) of group II mGluR in different types of somatic nociception.…”

“…Opioid-induced antinociceptive effects were enhanced by antagonists (15,16,45) and agonists (29) of group II mGluR in different types of somatic nociception. Currently, it is unknown whether this interaction between group II mGluR and opioid receptors occurs in visceral nociceptive mechanisms.…”

“…Recently, the interaction between mGluR and opioid receptors has also been identified in studies of opioid-induced antinociception (15,16,29,45). Opioid-induced antinociceptive effects were enhanced by antagonists (15,16,45) and agonists (29) of group II mGluR in different types of somatic nociception. Currently, it is unknown whether this interaction between group II mGluR and opioid receptors occurs in visceral nociceptive mechanisms.…”

“…An interaction between iGluR and opioid receptor mechanisms is believed to be important in pain pathways, because block of ionotropic Nmethyl-D-aspartate (NMDA) receptors enhances the antinociceptive effect of morphine (an opioid receptor agonist) (14,28,36,37). Recently, the interaction between mGluR and opioid receptors has also been identified in studies of opioid-induced antinociception (15,16,29,45). Opioid-induced antinociceptive effects were enhanced by antagonists (15,16,45) and agonists (29) of group II mGluR in different types of somatic nociception.…”