Mizoguchi Hirokazu, Watanabe Hiroyuki, Hayashi Takafumi, Sakurada Wataru, Sawai Toshiki, Fujimura Tsutomu, Sakurada Tsukasa, Sakurada Shinobu
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai, Japan.
J Pharmacol Exp Ther. 2006 Apr;317(1):362-8. doi: 10.1124/jpet.105.098293. Epub 2006 Jan 4.
The antinociception induced by i.t. or i.c.v. administration of endomorphins is mediated via mu-opioid receptors. However, although endomorphins do not have an appreciable affinity for kappa-opioid receptors, pretreatment with the kappa-opioid receptor antagonist norbinaltorphimine markedly reduces the antinociceptive response to i.c.v. or i.t. administered endomorphin-2 but not endomorphin-1. These results suggest that endomorphin-2 initially stimulates mu-opioid receptors, which subsequently induce the release of dynorphins that act on kappa-opioid receptors to produce antinociception. The present study was performed in mice to determine whether the release of dynorphins by i.t. administered endomorphin-2 is mediated through mu-opioid receptors to produce antinociception. Intrathecal pretreatment with an antiserum against dynorphin A-(1-17), but not against dynorphin B-(1-13) or alpha-neoendorphin, dose-dependently prevented the paw-withdrawal inhibition by endomorphin-2. The pretreatments with these antisera did not affect the endomorphin-1- or [D-Ala(2),MePhe(4),Gly(ol)(5)]enkephalin-induced paw-withdrawal inhibition. The attenuation of endomorphin-2-induced antinociception by i.t. pretreatment with an antiserum against dynorphin A-(1-17) or s.c. pretreatment with norbinaltorphimine was blocked dose-dependently by s.c. pretreatment with the mu-opioid receptor antagonist beta-funaltrexamine or the mu(1)-opioid receptor antagonist naloxonazine at ultra-low doses that are ineffective against mu-opioid receptor agonists. These results suggest that the spinal antinociception induced by endomorphin-2 is mediated through the stimulation of a distinct subtype of mu(1)-opioid receptor that induces the release of the endogenous kappa-opioid peptide dynorphin A-(1-17) in the spinal cord.
鞘内或脑室内注射内吗啡肽所诱导的抗伤害感受是通过μ-阿片受体介导的。然而，尽管内吗啡肽对κ-阿片受体没有明显的亲和力，但用κ-阿片受体拮抗剂诺宾那托啡预处理可显著降低脑室内或鞘内注射内吗啡肽-2后的抗伤害感受反应，而对内吗啡肽-1则无此作用。这些结果表明，内吗啡肽-2最初刺激μ-阿片受体，随后诱导强啡肽释放，强啡肽作用于κ-阿片受体产生抗伤害感受。本研究在小鼠中进行，以确定鞘内注射内吗啡肽-2所诱导的强啡肽释放是否通过μ-阿片受体介导以产生抗伤害感受。用抗强啡肽A-(1-17)的抗血清进行鞘内预处理，而非抗强啡肽B-(1-13)或α-新内啡肽的抗血清，可剂量依赖性地阻止内吗啡肽-2对爪部退缩的抑制作用。用这些抗血清预处理并不影响内吗啡肽-1或[D-丙氨酸(2)，甲硫氨酸苯丙氨酸(4)，甘氨酸(醇)(5)]脑啡肽诱导的爪部退缩抑制作用。用抗强啡肽A-(1-17)的抗血清进行鞘内预处理或用诺宾那托啡进行皮下预处理对内吗啡肽-2诱导的抗伤害感受的减弱作用，可被用μ-阿片受体拮抗剂β-芬太尼或超低剂量的μ(1)-阿片受体拮抗剂纳洛酮嗪进行皮下预处理剂量依赖性地阻断，这些超低剂量对μ-阿片受体激动剂无效。这些结果表明，内吗啡肽-2诱导的脊髓抗伤害感受是通过刺激一种独特的μ(1)-阿片受体亚型介导的，该亚型诱导脊髓内内源性κ-阿片肽强啡肽A-(1-17)的释放。
