Mogil J S, Marek P, Yirmiya R, Balian H, Sadowski B, Taylor A N, Liebeskind J C
Department of Psychology, University of California, Los Angeles 90024.
Brain Res. 1993 Jan 29;602(1):126-30. doi: 10.1016/0006-8993(93)90251-h.
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.
我们实验室最近的证据表明，N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801（地佐环平）可选择性拮抗小鼠应激诱导镇痛的非阿片类（即纳洛酮不敏感）机制。例如，我们最近证明，低剂量的MK-801（0.075毫克/千克，腹腔注射）可拮抗混合阿片类/非阿片类游泳应激诱导镇痛（SSIA）中的非阿片类成分，该镇痛是由在20摄氏度水中强迫游泳3分钟所致。由于已发现乙醇诱导镇痛（EIA）仅部分被纳洛酮减弱，我们推测MK-801会类似地阻断EIA的非阿片类成分。在对照小鼠以及为高（HA）或低（LA）SSIA选择性培育的小鼠中，研究了MK-801和阿片受体拮抗剂纳洛酮（10毫克/千克，腹腔注射）对乙醇（2.5克/千克，20%体积/体积，腹腔注射）产生的镇痛作用的影响。HA小鼠表现出的EIA显著多于对照组，而LA小鼠则显著少于对照组。纳洛酮和MK-801显著减弱了对照小鼠和HA小鼠的EIA，在这些品系中，两种拮抗剂联合给药可完全阻断EIA。在表现出极少EIA的LA小鼠中，纳洛酮而非MK-801可完全逆转EIA。这些发现为NMDA受体在镇痛的非阿片类机制中的作用提供了额外证据。为高和低SSIA选择性培育的小鼠也表现出高和低EIA这一发现表明，应激和乙醇对伤害感受过程的影响存在共同的介导作用。
