A cellular mechanism for the antinociceptive effect of a kappa opioid receptor agonist
A cellular mechanism for the antinociceptive effect of a kappa opioid receptor agonist
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DOI：
10.1016/s0304-3959(00)00464-4
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发表时间：
2001-04-01
期刊：
影响因子：
7.4
通讯作者：
Hammond, DL
中科院分区：
文献类型：
--
作者：
Ackley, MA;Hurley, RW;Hammond, DL
本研究采用一致的行为和电生理的方法来研究原型kappa阿片受体激动剂U69593在延髓头端腹内侧（RVM）的行动。在体外全细胞电压钳记录表明，浴应用U69593产生外向电流的原代细胞中的RVM。在占细胞群80%的次级细胞中，在不存在任何突触后效应的情况下，U69593对诱发的兴奋性突触后电流（EPSC）产生浓度依赖性且诺比纳尔托啡胺（norBNI）可逆的抑制作用。U69593还降低了次级细胞中自发性微小兴奋性突触后电流（mEPSC）的频率，但不降低其振幅。对次级细胞兴奋性输入的抑制与初级细胞的去抑制和抗伤害感受的产生是一致的。与此预期一致，通过微量注射U69593激活RVM中的κ阿片受体，产生了剂量依赖性的缩爪潜伏期增加，而norBNI则拮抗了这种增加。此外，在RVM中微量注射norBNI可拮抗全身给药U69593产生的缩爪潜伏期和热板潜伏期的增加。与此相反，在RVM中微量注射norBNI并没有拮抗由全身给药U69593产生的甩尾潜伏期的增加。此外，在RVM中微量注射U69593并不增加甩尾潜伏期。U69593的作用的高度测试依赖性表明，RVM中的神经元调节从尾部和后爪诱发的热伤害性反应的机制是不一致的。总的来说，这些数据表明，RVM是κ阿片受体激动剂的抗伤害作用的主要作用部位，其机制很可能涉及突触前抑制对次级细胞的兴奋性输入。因此，RVM中疼痛抑制神经元的去抑制可能是阿片受体激动剂产生抗伤害感受的常见机制，无论是通过直接抑制抑制性次级细胞，如μ阿片受体激动剂的情况下，还是通过减少对这些神经元的兴奋性驱动，如κ阿片受体激动剂的情况下。版权所有（C）2001国际疼痛研究协会。由Elsevier Science B.V.出版，版权所有。
This study used concordant behavioral and electrophysiological approaches to examine the actions of the prototypic kappa opioid receptor agonist U69593 in the rostral ventromedial medulla (RVM). In vitro whole-cell voltage clamp recordings indicated that bath application of U69593 produced outward currents in primary cells in the RVM. In secondary cells, which comprised 80% of the population, U69593 produced a concentration-dependent and norbinaltorphimine (norBNI)-reversible inhibition of evoked excitatory postsynaptic currents (EPSCs) in the absence of any postsynaptic effect. U69593 also decreased the frequency, but not the amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in secondary cells. The inhibition of excitatory inputs to secondary cells would be consonant with disinhibition of primary cells and the production of antinociception. Consistent with this expectation, the activation of kappa opioid receptors in the RVM by microinjection of U69593 produced a dose-dependent increase in paw-withdrawal latency that was antagonized by norBNI. Furthermore, microinjection of norBNI in the RVM antagonized the increases in paw-withdrawal latency and hot-plate latency produced by systemically-administered U69593. In contrast, microinjection of norBNI in the RVM did not antagonize the increase in tail-flick latency produced by systemically-administered U69593. Also, microinjection of U69593 in the RVM did not increase tail-flick latency. The highly test-dependent nature of U69593's effects suggests that the mechanisms by which neurons in the RVM modulate thermal nociceptive responses evoked from the tail and hindpaw are not uniform. Collectively, these data suggest that the RVM is a primary site of action for the antinociceptive actions of kappa opioid receptor agonists and that the mechanism most likely involves a presynaptic inhibition of excitatory inputs to secondary cells. Thus, disinhibition of pain inhibitory neurons in the RVM is likely to be a common mechanism by which opioid receptor agonists produce antinociception, whether by the direct inhibition of inhibitory secondary cells, as in the case of mu opioid receptor agonists, or by a reduction in the excitatory drive to these neurons, as in the case of kappa opioid receptor agonists. Copyright (C) 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.