Tambeli C H, Quang P, Levine J D, Gear R W
Department of Oral and Maxillofacial Surgery, Room C-522, Box 0440, University of California at San Francisco, San Francisco, CA 94143-0440, USA.
Eur J Neurosci. 2003 Dec;18(11):2999-3006. doi: 10.1111/j.1460-9568.2003.03031.x.
Noxious (i.e. painful) stimulation in the rat induces profound heterosegmental antinociception as demonstrated by the ability of either thermal stimulation (50 degrees C water) or subdermal capsaicin injection in the hindpaw to attenuate the nociceptive trigeminal jaw-opening reflex. Importantly, noxious stimulus-induced antinociception (NSIA) is mediated by endogenous opioids (as well as other neurotransmitters) in nucleus accumbens, as indicated by the ability of intra-accumbens administration of mu- or delta-opioid receptor antagonists to block NSIA. Although noxious peripheral stimulation is known to release excitatory neurotransmitters such as glutamate at the level of the spinal cord, the present study was designed to test the hypothesis that NSIA depends on further activation of spinal inhibitory receptors. This hypothesis was based on findings that inhibition of spinal processing (e.g. intrathecal local anaesthetic administration) also produces heterosegmental antinociception mediated by endogenous opioids in nucleus accumbens. Thus, to reconcile the paradoxical findings that both spinal excitation and inhibition appear to activate the same nucleus accumbens opioid-mediated antinociceptive mechanism, we investigated whether spinal administration of antagonists for inhibitory receptors would block the antinociceptive effect of subdermal capsaicin. We report that spinal administration of selective antagonists for mu-opioid (Cys2, Tyr3, Orn5, Pen7amide), kappa-opioid (nor-binaltorphimine), GABA-A (bicuculline), GABA-B (CGP 35348) and glycine (strychnine) receptors significantly reduced NSIA. The selective delta-opioid receptor antagonist naltrindole had no significant effect. These results, together with our previous findings, suggest that peripheral noxious stimuli release endogenous opioids, GABA and glycine in the spinal cord which, in turn, inhibit tonic pronociceptive spinal activity to produce heterosegmental antinociception mediated in nucleus accumbens.
大鼠体内的伤害性（即疼痛性）刺激会引发显著的异节段性抗伤害感受，这一点可通过热刺激（50摄氏度温水）或后爪皮下注射辣椒素减弱伤害性三叉神经张口反射的能力得以证明。重要的是，如伏隔核内注射μ-或δ-阿片受体拮抗剂能够阻断伤害性刺激诱导的抗伤害感受（NSIA）所示，伤害性刺激诱导的抗伤害感受是由伏隔核中的内源性阿片类物质（以及其他神经递质）介导的。尽管已知伤害性外周刺激会在脊髓水平释放兴奋性神经递质，如谷氨酸，但本研究旨在检验NSIA依赖于脊髓抑制性受体的进一步激活这一假说。该假说基于以下发现：抑制脊髓处理过程（如鞘内注射局部麻醉剂）也会产生由伏隔核内源性阿片类物质介导的异节段性抗伤害感受。因此，为了调和脊髓兴奋和抑制似乎都能激活同一伏隔核阿片类物质介导的抗伤害感受机制这一矛盾的发现，我们研究了脊髓给予抑制性受体拮抗剂是否会阻断皮下辣椒素的抗伤害感受作用。我们报告称，脊髓给予μ-阿片（Cys2、Tyr3、Orn5、Pen7酰胺）、κ-阿片（nor-苯并阿片肽）、GABA-A（荷包牡丹碱）、GABA-B（CGP 35348）和甘氨酸（士的宁）受体的选择性拮抗剂会显著降低NSIA。选择性δ-阿片受体拮抗剂纳曲吲哚没有显著作用。这些结果与我们之前的发现共同表明，外周伤害性刺激会在脊髓中释放内源性阿片类物质、GABA和甘氨酸，进而抑制脊髓的紧张性促伤害感受活动，以产生由伏隔核介导的异节段性抗伤害感受。
