Heinricher M M, McGaraughty S, Farr D A
Department of Neurological Surgery, Oregon Health Sciences University, Portland 97201, USA.
Pain. 1999 May;81(1-2):57-65. doi: 10.1016/s0304-3959(98)00271-1.
Two classes of neurons with distinct responses to opioids have been identified in the rostral ventromedial medulla (RVM), a region with a well-documented role in nociceptive modulation. 'Off-cells' are activated, indirectly, by opioids, and are likely to exert a net inhibitory effect on nociceptive processing. 'On-cells' are directly inhibited by opioids, and there is evidence that these neurons can, under various conditions, facilitate nociception. We showed previously that excitatory amino acid (EAA) neurotransmission is crucial to the nocifensor reflex-related on-cell burst, but plays little role in maintaining the ongoing activity of off-cells. The aim of the present study was to determine whether EAA transmission contributes to the activation of off-cells and the concomitant behavioral antinociception that follow systemic opioid administration. The non-selective EAA receptor antagonist kynurenate was infused into the RVM (1 nmol/200 nl) of lightly anesthetized rats prior to administration of morphine (1.5 mg/kg i.v). Off-cell, on-cell and neutral cell firing, as well as, tail flick response (TF) latencies were recorded. Kynurenate, significantly attenuated the characteristic opioid activation of off-cells. As a group, off-cells in kynurenate-treated animals did not become continuously active, and continued to exhibit tail-flick related pauses in firing. On-cell and neutral cell responses to opioid administration were unchanged. Opioid inhibition of the TF was also reduced, although baseline TF latency was unaffected, by RVM kynurenate. EAA-mediated activation of off-cells, thus has an important role in opioid analgesia. The present observations underscore the importance of excitatory interactions among opioid-sensitive nociceptive modulatory circuits for systemic morphine analgesia, suggesting that such interactions are a critical factor in the synergistic relationships which have been demonstrated among these sites.
延髓头端腹内侧区（RVM）是一个在伤害性调制中作用已得到充分证明的区域，现已确定其中存在两类对阿片类药物有不同反应的神经元。“脱细胞”被阿片类药物间接激活，可能对伤害性处理产生净抑制作用。“开细胞”被阿片类药物直接抑制，有证据表明这些神经元在各种条件下可促进伤害感受。我们先前表明，兴奋性氨基酸（EAA）神经传递对于与伤害性防御反射相关的开细胞爆发至关重要，但在维持脱细胞的持续活动中作用不大。本研究的目的是确定EAA传递是否有助于全身给予阿片类药物后脱细胞的激活以及随之而来的行为性抗伤害感受。在静脉注射吗啡（1.5mg/kg）之前，将非选择性EAA受体拮抗剂犬尿氨酸注入轻度麻醉大鼠的RVM（1nmol/200nl）。记录脱细胞、开细胞和中性细胞的放电以及甩尾反应（TF）潜伏期。犬尿氨酸显著减弱了脱细胞典型的阿片类药物激活。总体而言，经犬尿氨酸处理的动物中的脱细胞没有持续活跃，并继续表现出与甩尾相关的放电暂停。开细胞和中性细胞对阿片类药物给药的反应未改变。RVM注射犬尿氨酸后，阿片类药物对TF的抑制作用也降低了，尽管基线TF潜伏期未受影响。因此，EAA介导的脱细胞激活在阿片类镇痛中具有重要作用。本观察结果强调了阿片类敏感的伤害性调制回路之间的兴奋性相互作用对于全身吗啡镇痛的重要性，表明这种相互作用是这些部位之间已证明的协同关系中的关键因素。
