Parsons A M, Honda C N, Jia Y P, Budai D, Xu X J, Wiesenfeld-Hallin Z, Seybold V S
Department of Cell Biology and Neuroanatomy, University of Minnesota, Minneapolis 55455, USA.
Brain Res. 1996 Nov 11;739(1-2):263-75. doi: 10.1016/s0006-8993(96)00833-5.
Hyperalgesia is a characteristic of inflammation and is mediated, in part, by an increase in the excitability of spinal neurons. Although substance P does not appear to mediate fast synaptic events that underlie nociception in the spinal cord, it may contribute to the hyperalgesia and increased excitability of spinal neurons during inflammation induced by complete Freund's adjuvant. We examined the role of endogenous substance P in changes in the excitability of spinal neurons during adjuvant-induced, peripheral inflammation by determining the effect of a selective NK1 receptor antagonist (RP67580) on the nociceptive flexor reflex in adult rats. Experiments were conducted 2 or 3 days after injection of adjuvant. Animals exhibited moderate thermal hyperalgesia at this time. The flexor reflex was evoked by electrical stimulation of the sural nerve and was recorded in the ipsilateral hamstring muscles. The flexor reflex ipsilateral to the inflamed hindpaw was enhanced approximately two-fold compared to the flexor reflex evoked in untreated animals as determined by the number of potentials and the duration of the reflex. The enhanced reflex in adjuvant-treated animals was most likely due to an increase in the excitability of spinal interneurons because short-latency activity in the hamstring muscles did not differ between untreated animals and adjuvant-treated animals following electrical stimulation of the L5 dorsal root or the nerve innervating the muscle with a stimulus that was 1.3-1.5 times the threshold for excitation of A-fibers. Intrathecal administration of RP67580 (2.3 and 6.8 nmol) attenuated the flexor reflex evoked in adjuvant-treated animals, but had no effect in untreated animals. Intravenous or intraplantar injection of RP67580 (6.8 nmol) did not affect the flexor reflex in adjuvant-treated animals indicating a spinal action of the drug following intrathecal administration. RP68651, the enantiomer of RP67580, was without effect at doses up to 6.8 nmol, indicating that the effects of comparable doses of RP67580 were due to an action of the drug at NK1 receptors. However, intrathecal administration of 23 nmol of both drugs attenuated the reflex in adjuvant-treated and control animals indicating that effects of RP67580 at this dose were not mediated entirely by its action at NK1 receptors. Overall, these data suggest that endogenous substance P has a role in the increased excitability of spinal interneurons observed during persistent inflammation and support the hypothesis that substance P released in the spinal cord contributes to the hyperalgesia that accompanies adjuvant-induced persistent, peripheral inflammation.
痛觉过敏是炎症的一个特征，部分由脊髓神经元兴奋性增加介导。尽管P物质似乎不介导脊髓中伤害感受所基于的快速突触事件，但它可能在完全弗氏佐剂诱导的炎症期间导致痛觉过敏和脊髓神经元兴奋性增加。我们通过确定选择性NK1受体拮抗剂（RP67580）对成年大鼠伤害性屈肌反射的影响，研究了内源性P物质在佐剂诱导的外周炎症期间脊髓神经元兴奋性变化中的作用。在注射佐剂后2或3天进行实验。此时动物表现出中度热痛觉过敏。通过电刺激腓肠神经诱发屈肌反射，并在同侧腘绳肌中记录。与未处理动物诱发的屈肌反射相比，炎症后爪同侧的屈肌反射根据电位数量和反射持续时间增强了约两倍。佐剂处理动物中增强的反射最可能是由于脊髓中间神经元兴奋性增加，因为在电刺激L5背根或支配肌肉的神经且刺激强度为A纤维兴奋阈值的1.3 - 1.5倍后，未处理动物和佐剂处理动物腘绳肌中的短潜伏期活动没有差异。鞘内注射RP67580（2.3和6.8 nmol）减弱了佐剂处理动物诱发的屈肌反射，但对未处理动物没有影响。静脉内或足底注射RP67580（6.8 nmol）对佐剂处理动物的屈肌反射没有影响，表明鞘内给药后该药物具有脊髓作用。RP68651是RP67580的对映体，在剂量高达6.8 nmol时没有作用，表明相当剂量的RP67580的作用是由于该药物对NK1受体的作用。然而，鞘内注射23 nmol的两种药物都减弱了佐剂处理动物和对照动物的反射，表明该剂量的RP67580的作用并非完全由其对NK1受体的作用介导。总体而言，这些数据表明内源性P物质在持续性炎症期间观察到的脊髓中间神经元兴奋性增加中起作用，并支持脊髓中释放的P物质导致佐剂诱导的持续性外周炎症伴随的痛觉过敏这一假说。
