Bie Bihua, Pan Zhizhong Z
Department of Symptom Research, The University of Texas-MD Anderson Cancer Center, Houston, Texas 77030, USA.
J Neurosci. 2003 Aug 13;23(19):7262-8. doi: 10.1523/JNEUROSCI.23-19-07262.2003.
Glutamate neurotransmission plays an important role in the processing of pain and in chronic opioid-induced neural and behavioral plasticity, such as opioid withdrawal and opioid dependence. Kappa-opioid receptors also have been implicated in acute opioid modulation of pain and chronic opioid-induced plasticity, both of which are primarily mediated by mu-opioid receptors. Using whole-cell patch clamp recordings in brain slices in vitro and system analysis of pain behaviors in rats in vivo, this study investigated the functional role of glutamate synaptic transmission and kappa-opioid receptors in two behavioral pain conditions: m-opioid-induced analgesia (decreased pain) and mu-opioid withdrawal-induced hyperalgesia (increased pain). In the nucleus raphe magnus (NRM), a brainstem structure that controls spinal pain transmission, we found that kappa-receptor agonists presynaptically inhibited glutamate synaptic currents in both of the two cell types that are thought to respectively inhibit or facilitate spinal pain transmission. In rats, both glutamate receptor antagonists and the kappa agonist microinjected into the NRM attenuated mu-opioid-induced analgesia, which is most likely mediated through activation of such pain-inhibiting neurons. However, during opioid abstinence-induced withdrawal, the same doses of glutamate receptor antagonists and the kappa agonist administered in the NRM suppressed the withdrawal-induced hyperalgesia, which is thought to be mediated by activation of those pain-facilitating neurons during opioid withdrawal. These results demonstrate that kappa-opioid receptors antagonize mu-receptor-induced effects in both analgesic and hyperalgesic states, and suggest inhibition of glutamate synaptic transmission as a presynaptic mechanism for the kappa antagonism of these two mu receptor-mediated actions.
谷氨酸能神经传递在疼痛处理以及慢性阿片类药物诱导的神经和行为可塑性（如阿片类药物戒断和阿片类药物依赖）中发挥着重要作用。κ-阿片受体也与阿片类药物对疼痛的急性调节以及慢性阿片类药物诱导的可塑性有关，而这两者主要由μ-阿片受体介导。本研究利用体外脑片的全细胞膜片钳记录以及体内大鼠疼痛行为的系统分析，探究了谷氨酸突触传递和κ-阿片受体在两种行为性疼痛状态下的功能作用：μ-阿片诱导的镇痛（疼痛减轻）和μ-阿片戒断诱导的痛觉过敏（疼痛加剧）。在中缝大核（NRM）这个控制脊髓疼痛传递的脑干结构中，我们发现κ-受体激动剂在突触前抑制了两种细胞类型中的谷氨酸突触电流，这两种细胞类型分别被认为抑制或促进脊髓疼痛传递。在大鼠中，将谷氨酸受体拮抗剂和κ-激动剂微量注射到NRM中，均可减弱μ-阿片诱导的镇痛作用，这很可能是通过激活此类疼痛抑制神经元介导的。然而，在阿片类药物戒断诱导的戒断过程中，在NRM中给予相同剂量的谷氨酸受体拮抗剂和κ-激动剂可抑制戒断诱导的痛觉过敏，这被认为是由阿片类药物戒断期间那些疼痛促进神经元的激活介导的。这些结果表明，κ-阿片受体在镇痛和痛觉过敏状态下均拮抗μ-受体诱导的效应，并提示抑制谷氨酸突触传递是κ-受体拮抗这两种μ-受体介导作用的突触前机制。
