Morgan Michael M, Bobeck Erin N, Ingram Susan L
Department of Psychology, Washington State University Vancouver, 14204 NE Salmon Creek Ave., Vancouver, WA 98686, USA.
Brain Res. 2009 Oct 27;1295:59-66. doi: 10.1016/j.brainres.2009.07.100. Epub 2009 Aug 5.
The periaqueductal gray (PAG) plays an important role in morphine antinociception and tolerance. Co-localization of mu-opioid and NMDA receptors on dendrites in the PAG suggests that glutamate may modulate morphine antinociception. Moreover, the involvement of glutamate in spinally mediated tolerance to morphine suggests that glutamate receptors may contribute to PAG mediated tolerance. These hypotheses were tested by microinjecting glutamate receptor antagonists and morphine into the ventrolateral PAG (vPAG) of the rat. Microinjection of the non-specific glutamate receptor antagonist kynurenic acid or the NMDA receptor antagonist MK-801 into the vPAG did not affect nociception. However, co-administration of these antagonists with morphine into the vPAG enhanced the acute antinociceptive effects of morphine as measured by a leftward shift in the morphine dose-response curves. Repeated microinjections of morphine into the vPAG caused a rightward shift in the dose-response curve for antinociception whether the glutamate receptor antagonists kynurenic acid or MK-801 were co-administered or not. The lack of effect of microinjecting glutamate receptor antagonists into the vPAG indicates that tonic glutamate release in the PAG does not contribute to nociceptive tone. That these antagonists enhance morphine antinociception indicates that endogenous glutamate counteracts the antinociceptive effect of morphine in the vPAG. However, this compensatory glutamate release does not contribute to tolerance to the antinociceptive effects of microinjecting morphine into the vPAG. Previous research showing that glutamate contributes to spinal mechanisms of tolerance indicate that different tolerance mechanisms are engaged in the vPAG and spinal cord.
中脑导水管周围灰质（PAG）在吗啡镇痛及耐受中发挥重要作用。PAG中树突上的μ-阿片受体与NMDA受体共定位表明，谷氨酸可能调节吗啡镇痛。此外，谷氨酸参与脊髓介导的吗啡耐受提示谷氨酸受体可能参与PAG介导的耐受。通过向大鼠腹外侧PAG（vPAG）微量注射谷氨酸受体拮抗剂和吗啡对这些假说进行了验证。向vPAG微量注射非特异性谷氨酸受体拮抗剂犬尿喹啉酸或NMDA受体拮抗剂MK-801不影响痛觉感受。然而，将这些拮抗剂与吗啡共同注射到vPAG中时，如通过吗啡剂量-反应曲线左移所测，可增强吗啡的急性镇痛作用。无论是否共同注射谷氨酸受体拮抗剂犬尿喹啉酸或MK-801，向vPAG重复微量注射吗啡均导致镇痛剂量-反应曲线右移。向vPAG微量注射谷氨酸受体拮抗剂无效表明PAG中谷氨酸的紧张性释放对痛觉感受基调无作用。这些拮抗剂增强吗啡镇痛表明内源性谷氨酸抵消了吗啡在vPAG中的镇痛作用。然而，这种代偿性谷氨酸释放并不参与对向vPAG微量注射吗啡镇痛作用的耐受。先前研究表明谷氨酸参与脊髓耐受机制，提示vPAG和脊髓中存在不同的耐受机制。
