Lomas Lisa M, Barrett Andrew C, Terner Jolan M, Lysle Donald T, Picker Mitchell J
Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3270, USA.
Psychopharmacology (Berl). 2007 Apr;191(2):273-85. doi: 10.1007/s00213-006-0663-1. Epub 2007 Jan 16.
Sex differences in the potency of the antinociceptive effects of kappa opioids have been reported in various acute pain models with evidence suggesting that these sex differences are mediated by activity in the N-methyl-D: -aspartate (NMDA) system.
The purpose of the present study was to evaluate sex differences in the antihyperalgesic actions of selected kappa and mixed-action opioids in a persistent pain model and determine if the NMDA system modulates these effects in a sexually dimorphic manner.
Using gonadally intact male and female F344 rats, hyperalgesia was induced by local administration of capsaicin in the tail, after which the tail was immersed in a mildly noxious thermal stimulus (45 degrees C water), and tail-withdrawal latency measured. Opioids were then administered systemically (s.c.) and locally (in the tail) alone, and in selected combinations with the noncompetitive NMDA antagonist dextromethorphan.
When administered systemically and locally, the kappa opioids spiradoline, U69,593 and U50,488, and the mixed-action opioids butorphanol and nalbuphine, produced dose-dependent antihyperalgesic effects. Whereas the kappa opioids were generally more potent in males, sex differences were not observed with the mixed-action opioids. Peripheral receptor activity was confirmed for local administration of kappa opioids by the antagonism observed after local, but not intracerebroventricular (i.c.v.), administration of the kappa antagonist nor-binaltorphamine (nor-BNI). Dextromethorphan was equally potent in attenuating the antihyperalgesia induced by kappa opioids in both males and females.
These findings demonstrate sex differences in kappa opioid activity in a persistent pain model. Although an NMDA antagonist blocked the effects of kappa opioids in this model, these effects were not sexually dimorphic as reported in most acute pain models.
在各种急性疼痛模型中均报道了κ阿片类药物镇痛作用效力的性别差异，有证据表明这些性别差异是由N-甲基-D-天冬氨酸（NMDA）系统的活性介导的。
本研究的目的是评估在持续性疼痛模型中，选定的κ阿片类药物和混合作用阿片类药物的抗痛觉过敏作用的性别差异，并确定NMDA系统是否以性别二态性方式调节这些作用。
使用性腺完整的雄性和雌性F344大鼠，通过在尾巴局部施用辣椒素来诱导痛觉过敏，之后将尾巴浸入轻度有害的热刺激（45℃水）中，并测量甩尾潜伏期。然后单独全身（皮下）和局部（在尾巴中）给予阿片类药物，并与非竞争性NMDA拮抗剂右美沙芬以选定的组合给予。
全身和局部给药时，κ阿片类药物spiradoline、U69,593和U50,488，以及混合作用阿片类药物布托啡诺和纳布啡产生剂量依赖性抗痛觉过敏作用。虽然κ阿片类药物通常在雄性中更有效，但混合作用阿片类药物未观察到性别差异。通过在局部（而非脑室内）给予κ拮抗剂去甲二丙诺啡（nor-BNI）后观察到的拮抗作用，证实了局部给予κ阿片类药物的外周受体活性。右美沙芬在减轻雄性和雌性中由κ阿片类药物诱导的抗痛觉过敏方面同样有效。
这些发现证明了在持续性疼痛模型中κ阿片类药物活性存在性别差异。虽然NMDA拮抗剂在该模型中阻断了κ阿片类药物的作用，但这些作用并不像大多数急性疼痛模型中报道的那样具有性别二态性。
