Ackley Michael A, Hurley Robert W, Virnich Daniel E, Hammond Donna L
Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637, USA The Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA.
Pain. 2001 Apr;91(3):377-388. doi: 10.1016/S0304-3959(00)00464-4.
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.
本研究采用一致的行为学和电生理学方法，来研究典型的κ阿片受体激动剂U69593在延髓头端腹内侧区（RVM）的作用。体外全细胞电压钳记录表明，在RVM的原代细胞中，浴加U69593可产生外向电流。在占细胞总数80%的二代细胞中，U69593在无任何突触后效应的情况下，对诱发的兴奋性突触后电流（EPSC）产生浓度依赖性且可被纳洛酮苯并咪唑（norBNI）逆转的抑制作用。U69593还降低了二代细胞中自发微小兴奋性突触后电流（mEPSC）的频率，但未改变其幅度。对二代细胞兴奋性输入的抑制与原代细胞的去抑制及抗伤害感受的产生相一致。与这一预期相符，通过微量注射U69593激活RVM中的κ阿片受体会使爪部撤离潜伏期剂量依赖性增加，且该作用可被norBNI拮抗。此外，在RVM中微量注射norBNI可拮抗全身给药U69593所引起的爪部撤离潜伏期和热板潜伏期增加。相反，在RVM中微量注射norBNI并不能拮抗全身给药U69593所引起的甩尾潜伏期增加。而且，在RVM中微量注射U69593并不会增加甩尾潜伏期。U69593作用高度依赖测试的性质表明，RVM中神经元调节从尾部和后爪诱发的热痛觉反应的机制并不一致。总体而言，这些数据表明RVM是κ阿片受体激动剂抗伤害感受作用的主要作用部位，且其机制很可能涉及对二代细胞兴奋性输入的突触前抑制。因此，RVM中疼痛抑制神经元的去抑制很可能是阿片受体激动剂产生抗伤害感受的常见机制，无论是像μ阿片受体激动剂那样直接抑制抑制性二代细胞，还是像κ阿片受体激动剂那样减少对这些神经元的兴奋性驱动。
