Dong Xiao-Wei, Williams Patricia A, Jia Yu-Ping, Priestley Tony
CNS/Cardiovascular Biological Research, Schering-Plough Research Institute, K-15-2-2600, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Pain. 2002 Apr;96(3):309-318. doi: 10.1016/S0304-3959(01)00460-2.
Neurogenic inflammation is an inflammatory response of peripheral tissue to vasoactive substances released from sensory afferent terminals. It can be triggered via a local axon reflex and by dorsal root reflex (DRR) activity involving the spinal cord. Nociceptin, an endogenous ligand for the opioid receptor-like (ORL-1) G-protein coupled receptor, has been found to inhibit the local axon reflex-mediated neurogenic inflammation by suppressing the release of vasoactive neuropeptides from sensory afferent terminals. The present study was to explore the role of spinal ORL-1 receptors in the modulation of DRR-induced neurogenic inflammation. We first examined the effect of nociceptin on DRR by recording dorsal root potentials (DRPs) and the associated antidromic discharges, evoked by electrical stimulation of an adjacent dorsal root in an in vitro neonatal rat spinal cord preparation. Nociceptin reversibly inhibited the DRP in a concentration-dependent manner (IC50: approximately 45 nM, maximal inhibition: approximately 50%), an effect that was antagonized by the ORL-1 receptor antagonist, J-113397. Neurochemical studies demonstrated that nociceptin (10 microM) also produced an approximately 40% reduction in gamma amino butyric acid (GABA) release evoked by electrical stimulation of neonatal rat spinal cord slices. On the other hand, nociceptin had no effect on exogenous GABA-evoked DRP. These findings suggest that the nociceptin-induced inhibition of the DRP is most likely due to the suppression of GABA release, the principle transmitter mediating DRP, from GABAergic neurons that are pre-synaptic to primary afferent terminals. Finally, in order to explore the physiological significance of such modulation in a fully integrated system, we evaluated the effect of intrathecally administered nociceptin on capsaicin-induced acute cutaneous neurogenic inflammation in rat hind paw, quantified by examining the degree of paw edema in anesthetized rats. The magnitude of capsaicin-induced increase of paw thickness was reduced by approximately 50% from 31+/-1.34% (n=6) to 15+/-1.63% (n=8; P<0.05) by nociceptin (10 micromol). We conclude that spinal ORL-1 receptors can modulate neurogenic inflammation by suppressing the GABAergic neuronal activity in the dorsal horn that is responsible for generating DRRs.
神经源性炎症是外周组织对感觉传入神经末梢释放的血管活性物质的炎症反应。它可通过局部轴突反射和涉及脊髓的背根反射（DRR）活动引发。孤啡肽是阿片受体样（ORL-1）G蛋白偶联受体的内源性配体，已发现其通过抑制感觉传入神经末梢释放血管活性神经肽来抑制局部轴突反射介导的神经源性炎症。本研究旨在探讨脊髓ORL-1受体在调节DRR诱导的神经源性炎症中的作用。我们首先通过记录背根电位（DRP）和相关的逆向放电来研究孤啡肽对DRR的影响，这些电位和放电是在新生大鼠脊髓体外制备中通过电刺激相邻背根诱发的。孤啡肽以浓度依赖性方式可逆地抑制DRP（IC50：约45 nM，最大抑制：约50%），ORL-1受体拮抗剂J-113397可拮抗这一作用。神经化学研究表明，孤啡肽（10 microM）还使新生大鼠脊髓切片电刺激诱发的γ-氨基丁酸（GABA）释放减少约40%。另一方面，孤啡肽对外源性GABA诱发的DRP无影响。这些发现表明，孤啡肽诱导的DRP抑制很可能是由于抑制了GABA的释放，GABA是介导DRP的主要递质，它来自初级传入神经末梢突触前的GABA能神经元。最后，为了在一个完全整合的系统中探讨这种调节的生理意义，我们评估了鞘内注射孤啡肽对辣椒素诱导的大鼠后爪急性皮肤神经源性炎症的影响，通过检查麻醉大鼠爪部水肿程度进行量化。孤啡肽（10微摩尔）使辣椒素诱导的爪厚度增加幅度从31±1.34%（n = 6）降低约50%至15±1.63%（n = 8；P<0.05）。我们得出结论，脊髓ORL-1受体可通过抑制背角中负责产生DRR的GABA能神经元活动来调节神经源性炎症。
