Opioid and nonopioid swim stress-induced analgesia: a parametric analysis in mice.

Environmental stress causes the activation of two types of endogenous pain inhibitory systems in animals: opioid analgesia is antagonized by opiate receptor blockers (e.g., naloxone and naltrexone), whereas analgesia produced by nonopioid systems is insensitive to such antagonism. A large literature documents that the parameters of the laboratory stressor will determine the neurochemical identity of the resultant analgesia. In rats, low severity stressors produce opioid analgesia and higher severity stressors produce nonopioid analgesia. A recent parametric analysis of swim stress-induced analgesia (SSIA) in the female Quackenbush mouse, however, observed the opposite pattern. The present study is a parametric analysis of SSIA using a range of swim temperatures (15-38 degrees C), swim durations (45 s to 7 min), and genetic models [male Swiss-Webster mice, and mice selectively bred from this outbred strain for high (HA), low (LA), or control SSIA]. We find that in nonselected mice low severity swims (i.e., warm temperature, short duration) produce naloxone-sensitive opioid SSIA, whereas high severity swims (i.e., cold temperature, long duration) produce nonopioid SSIA. This pattern is also seen in HA mice displaying very high analgesic magnitudes, but not in LA mice displaying minimal SSIA. In the selectively bred mice, analgesia and hypothermia from forced swimming are positively correlated, but can be dissociated both genetically and neurochemically. Furthermore, swimming in body temperature (38 degrees C) water produces analgesia without concommitant hypothermia, and the increased magnitude of 38 degrees C SSIA displayed by HA mice over control levels is entirely opioid.

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 degrees 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.