Antagonism of the non-opioid component of ethanol-induced analgesia by the NMDA receptor antagonist MK-801

Recent evidence from our laboratory suggests that the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) selectively antagonizes non-opioid (i.e. naloxone-insensitive) mechanisms of stress-induced analgesia in mice. For example, we have recently demonstrated that a low dose of MK-801 (0.075 mg/kg, i.p.) antagonizes the non-opioid component of a mixed opioid/non-opioid swim stress-induced analgesia (SSIA) resulting from forced swimming for 3 min in 20°C water. Since ethanol-induced analgesia (EIA) has been found to be only partially attenuated by naloxone, we hypothesized that MK-801 would similarly block the non-opioid component of EIA. The effects of MK-801 and of the opioid receptor antagonist naloxone (10 mg/kg, i.p.) on analgesia produced by ethanol (2.5 g/kg in 20% vol/vol, i.p.) were studied in control mice and in mice selectively bred for high (HA) or low (LA) SSIA. HA mice showed significantly more, and LA mice significantly less, EIA than controls. Naloxone and MK-801 significantly attenuated EIA in control and HA mice, and in these lines the combined administration of both antagonists blocked EIA completely. In LA mice, which displayed very little EIA, naloxone but not MK-801 reversed EIA completely. These findings provide additional evidence for the role of the NMDA receptor in non-opioid mechanisms of analgesia. The finding that mice selectively bred for high and low SSIA also display high and low EIA suggests common mediation of the effects of stress and ethanol on antinociceptive processes.