Glutamate modulation of antinociception, but not tolerance, produced by morphine microinjection into the periaqueductal gray of the rat.
Glutamate modulation of antinociception, but not tolerance, produced by morphine microinjection into the periaqueductal gray of the rat.
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DOI：
10.1016/j.brainres.2009.07.100
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发表时间：
2009-10-27
期刊：
影响因子：
2.9
通讯作者：
Ingram, Susan L.
中科院分区：
文献类型：
--
作者：
Morgan, Michael M.;Bobeck, Erin N.;Ingram, Susan L.
中脑导水管周围灰质（PAG）在吗啡镇痛和耐受中起重要作用。PAG树突上μ阿片受体和NMDA受体的共定位表明谷氨酸可能调节吗啡的抗伤害作用。此外，谷氨酸参与脊髓介导的吗啡耐受表明，谷氨酸受体可能有助于PAG介导的耐受。通过在大鼠腹外侧PAG（vPAG）内微量注射谷氨酸受体拮抗剂和吗啡来验证这些假设。将非特异性谷氨酸受体拮抗剂犬尿烯酸或NMDA受体拮抗剂MK-801微量注射到vPAG中不影响伤害性感受。然而，共同管理这些拮抗剂与吗啡进入vPAG增强急性镇痛作用的吗啡，吗啡的剂量-反应曲线的快速移动。无论是否同时给予谷氨酸受体拮抗剂犬尿烯酸或MK-801，重复向vPAG中微量注射吗啡均导致抗伤害感受的剂量反应曲线发生显著偏移。将谷氨酸受体拮抗剂微量注射到vPAG中缺乏效果表明PAG中的紧张性谷氨酸释放不有助于伤害性紧张。这些拮抗剂增强吗啡的抗伤害感受，表明内源性谷氨酸抵消了吗啡在vPAG中的抗伤害感受作用。然而，这种补偿性谷氨酸释放并不有助于对vPAG微量注射吗啡的抗伤害作用的耐受性。先前的研究表明，谷氨酸有助于脊髓耐受机制，表明vPAG和脊髓中参与了不同的耐受机制。
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.
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