Sakurada S, Hayashi T, Yuhki M, Orito T, Zadina J E, Kastin A J, Fujimura T, Murayama K, Sakurada C, Sakurada T, Narita M, Suzuki T, Tan-no K, Tseng L F
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Sendai 981-8558, Japan.
Eur J Pharmacol. 2001 Sep 21;427(3):203-10. doi: 10.1016/s0014-2999(01)01238-9.
Two highly selective mu-opioid receptor agonists, endomorphin-1 and endomorphin-2, have been identified and postulated to be endogenous ligands for mu-opioid receptors. Intrathecal (i.t.) administration of endomorphin-1 and endomorphin-2 at doses from 0.039 to 5 nmol dose-dependently produced antinociception with the paw-withdrawal test. The paw-withdrawal inhibition rapidly reached its peak at 1 min, rapidly declined and returned to the pre-injection levels in 20 min. The inhibition of the paw-withdrawal responses to endomorphin-1 and endomorphin-2 at a dose of 5 nmol observed at 1 and 5 min after injection was blocked by pretreatment with a non-selective opioid receptor antagonist naloxone (1 mg/kg, s.c.). The antinociceptive effect of endomorphin-2 was more sensitive to the mu (1)-opioid receptor antagonist, naloxonazine than that of endomorphin-1. The endomorphin-2-induced paw-withdrawal inhibition at both 1 and 5 min after injection was blocked by pretreatment with kappa-opioid receptor antagonist nor-binaltorphimine (10 mg/kg, s.c.) or the delta(2)-opioid receptor antagonist naltriben (0.6 mg/kg, s.c.) but not the delta(1)-opioid receptor antagonist 7-benzylidine naltrexone (BNTX) (0.6 mg/kg s.c.). In contrast, the paw-withdrawal inhibition induced by endomorphin-1 observed at both 1 and 5 min after injection was not blocked by naloxonazine (35 mg/kg, s.c.), nor-binaltorphimine (10 mg/kg, s.c.), naltriben (0.6 mg/kg, s.c.) or BNTX (0.6 mg/kg s.c.). The endomorphin-2-induced paw-withdrawal inhibition was blocked by the pretreatment with an antiserum against dynorphin A-(1-17) or [Met(5)]enkephalin, but not by antiserum against dynorphin B-(1-13). Pretreatment with these antisera did not affect the endomorphin-1-induced paw-withdrawal inhibition. Our results indicate that endomorphin-2 given i.t. produces its antinociceptive effects via the stimulation of mu (1)-opioid receptors (naloxonazine-sensitive site) in the spinal cord. The antinociception induced by endomophin-2 contains additional components, which are mediated by the release of dynorphin A-(1-17) and [Met(5)]enkephalin which subsequently act on kappa-opioid receptors and delta(2)-opioid receptors to produce antinociception.
两种高选择性的μ-阿片受体激动剂，内吗啡肽-1和内吗啡肽-2，已被鉴定并推测为μ-阿片受体的内源性配体。鞘内注射（i.t.）剂量为0.039至5 nmol的内吗啡肽-1和内吗啡肽-2，通过爪部退缩试验剂量依赖性地产生抗伤害感受作用。爪部退缩抑制在1分钟时迅速达到峰值，随后迅速下降，并在20分钟内恢复到注射前水平。注射后1分钟和5分钟时，5 nmol剂量的内吗啡肽-1和内吗啡肽-2对爪部退缩反应的抑制作用，可被非选择性阿片受体拮抗剂纳洛酮（1 mg/kg，皮下注射）预处理所阻断。内吗啡肽-2的抗伤害感受作用比内吗啡肽-1对μ（1）-阿片受体拮抗剂纳洛酮嗪更敏感。注射后1分钟和5分钟时，内吗啡肽-2诱导的爪部退缩抑制作用，可被κ-阿片受体拮抗剂去甲二氢吗啡酮（10 mg/kg，皮下注射）或δ（2）-阿片受体拮抗剂纳曲苄（0.6 mg/kg，皮下注射）预处理所阻断，但不能被δ（1）-阿片受体拮抗剂7-苄叉基纳曲酮（BNTX）（0.6 mg/kg皮下注射）所阻断。相比之下，注射后1分钟和5分钟时观察到的内吗啡肽-1诱导的爪部退缩抑制作用，不受纳洛酮嗪（35 mg/kg，皮下注射）、去甲二氢吗啡酮（10 mg/kg，皮下注射）、纳曲苄（0.6 mg/kg皮下注射）或BNTX（0.6 mg/kg皮下注射）的影响。内吗啡肽-2诱导的爪部退缩抑制作用，可被抗强啡肽A-（1-17）或[Met（5）]脑啡肽的抗血清预处理所阻断，但不能被抗强啡肽B-（1-13）的抗血清所阻断。用这些抗血清预处理不影响内吗啡肽-1诱导的爪部退缩抑制作用。我们的结果表明，鞘内注射内吗啡肽-2通过刺激脊髓中的μ（1）-阿片受体（纳洛酮嗪敏感位点）产生其抗伤害感受作用。内吗啡肽-2诱导的抗伤害感受作用包含其他成分，这些成分由强啡肽A-（1-17）和[Met（5）]脑啡肽的释放介导，随后作用于κ-阿片受体和δ（2）-阿片受体以产生抗伤害感受作用。
