Nozaki-Taguchi N, Yamamoto T
Department of Anesthesiology, School of Medicine, Chiba University, Japan.
Anesth Analg. 1998 Aug;87(2):388-93. doi: 10.1097/00000539-199808000-00028.
Nitric oxide (NO) has been reported to enhance the analgesic effect of the peripherally administered mu-opioid receptor agonists, but the role of NO on the analgesic effect of the peripherally administered kappa and delta opioid receptor agonists is still unclear. We examined the effects of peripherally applied kappa- and delta-opioid receptor agonists and of their interactions with the NO-releasing drug, FK409, on the behavioral response to intraplantar injection of formalin in rats (the formalin test). The formalin injection results in a biphasic appearance of agitation behavior, consisting of the early (Phase 1; 0-9 min) and late (Phase 2; 10-60 min) responses. The active enantiomer of kappa-opioid receptor agonist, (-)U50,488H, dose-dependently suppressed the agitation response in both phases of the formalin test when applied peripherally. A peripheral delta-opioid receptor agonist, [D-Pen(2,5)] enkephalin (DPDPE), suppressed only Phase 2 of the formalin test. Local application of FK409 after the administration of a subthreshold dose of each opioid resulted in a dose-dependent decrease in the Phase 1, but not Phase 2, response to the formalin test for both agonists. Interactions between peripheral opioids and FK409 were reversed with both naloxone and carboxy-PTIO (NO scavenger). Systemic injections of either a kappa- or delta-agonist had no interaction with peripherally applied FK409. Peripheral FK409 alone did not have any significant effect on the formalin test. These data indicate that the antinociceptive effects of peripherally applied kappa- and delta-opioid agonists on the formalin test are potentiated by the local action of NO.
The analgesic effects of peripherally applied kappa- and delta-opioid receptor agonists during inflammation induced by formalin injection in the rat are, at least partly, mediated by the NO-cGMP pathway.
据报道，一氧化氮（NO）可增强外周给予的μ阿片受体激动剂的镇痛作用，但NO对外周给予的κ和δ阿片受体激动剂镇痛作用的影响仍不清楚。我们研究了外周应用κ和δ阿片受体激动剂及其与释放NO的药物FK409相互作用对大鼠足底注射福尔马林后行为反应（福尔马林试验）的影响。福尔马林注射导致激动行为呈双相出现，包括早期（第1阶段；0 - 9分钟）和晚期（第2阶段；10 - 60分钟）反应。κ阿片受体激动剂的活性对映体（-）U50,488H外周应用时，在福尔马林试验的两个阶段均剂量依赖性地抑制激动反应。外周δ阿片受体激动剂[D - Pen(2,5)]脑啡肽（DPDPE）仅抑制福尔马林试验的第2阶段。在给予每种阿片类药物阈下剂量后局部应用FK409，导致两种激动剂对福尔马林试验的第1阶段反应呈剂量依赖性降低，但对第2阶段反应无影响。外周阿片类药物与FK409之间的相互作用可被纳洛酮和羧基 - PTIO（NO清除剂）逆转。全身注射κ或δ激动剂与外周应用的FK409无相互作用。单独外周应用FK409对福尔马林试验无任何显著影响。这些数据表明，外周应用的κ和δ阿片激动剂在福尔马林试验中的抗伤害感受作用通过NO的局部作用而增强。
外周应用κ和δ阿片受体激动剂在大鼠福尔马林注射诱导的炎症过程中的镇痛作用至少部分由NO - cGMP途径介导。
