Al-Khrasani Mahmoud, Spetea Mariana, Friedmann Tamas, Riba Pal, Király Kornel, Schmidhammer Helmut, Furst Susanna
Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
Brain Res Bull. 2007 Oct 19;74(5):369-75. doi: 10.1016/j.brainresbull.2007.07.008. Epub 2007 Jul 30.
Peripheral micro-opioid receptors (MOR) have emerged as important components of inhibitory nociceptive pathways. Here, the antinociceptive effects of MOR agonists, the 6beta-glycine derivative of 14-O-methyloxymorphone (HS-731), DAMGO and morphine were evaluated in a mouse model of visceral pain. The abdominal acetic acid-induced writhing test was used to examine the peripheral, preemptive antinociceptive opioid action on visceral nociception. HS-731 administered subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) dose-dependently and completely inhibited writhing, being 24-598-fold more potent, depending on the administration route, than two selective MOR agonists, the enkephalin analogue [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]enkephalin (DAMGO) and morphine. A longer duration of action (2-3 h) was induced by HS-731 given before acetic acid, while shorter effect was produced by morphine (30-60 min) and DAMGO (30-45 min). The antinociceptive effects of systemic opioids were reversed by the s.c. opioid antagonist, naloxone. Blocking of central MOR by the selective MOR antagonist D-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP, i.c.v.) resulted in a significant reduction of antinociception of s.c. morphine, whereas it completely failed to antagonize the effects of systemic HS-731 or DAMGO. In in vitro studies, HS-731 and DAMGO, but not morphine showed high intrinsic efficacy, naltrexone-sensitive agonist effect at MOR of the rat vas deferens. These data demonstrate that selective activation of peripheral MOR by systemic s.c. HS-731 or DAMGO produces potent peripheral, preemptive visceral antinociception, while morphine's effects are mediated primarily through central mechanisms. Our findings support the role of peripheral MOR in the pathology of pain states involving sensitization of peripheral nociceptors.
外周微阿片受体（MOR）已成为伤害性感受抑制通路的重要组成部分。在此，在小鼠内脏痛模型中评估了MOR激动剂、14 - O - 甲基羟吗啡酮的6β - 甘氨酸衍生物（HS - 731）、DAMGO和吗啡的抗伤害感受作用。采用腹部醋酸诱导扭体试验来检测外周、预防性阿片类药物对内脏伤害感受的抗伤害作用。皮下（s.c.）或脑室内（i.c.v.）给予HS - 731剂量依赖性地完全抑制扭体反应，根据给药途径不同，其效力比两种选择性MOR激动剂脑啡肽类似物[D - Ala(2),N - Me - Phe(4),Gly - ol(5)]脑啡肽（DAMGO）和吗啡高24 - 598倍。在醋酸给药前给予HS - 731可诱导更长的作用持续时间（2 - 3小时），而吗啡（30 - 60分钟）和DAMGO（30 - 45分钟）产生的作用持续时间较短。全身给予阿片类药物的抗伤害感受作用可被皮下注射阿片类拮抗剂纳洛酮逆转。选择性MOR拮抗剂D - Phe - Cys - Tyr - d - Trp - Arg - Thr - Pen - Thr - NH₂（CTAP，i.c.v.）阻断中枢MOR可导致皮下注射吗啡的抗伤害感受作用显著降低，而它完全不能拮抗全身给予HS - 731或DAMGO的作用。在体外研究中，HS - 731和DAMGO，但吗啡未显示出在大鼠输精管MOR上的高内在效能、纳曲酮敏感的激动剂效应。这些数据表明，全身皮下给予HS - 731或DAMGO选择性激活外周MOR可产生强大的外周、预防性内脏抗伤害感受作用，而吗啡的作用主要通过中枢机制介导。我们的研究结果支持外周MOR在涉及外周伤害感受器敏化的疼痛状态病理过程中的作用。
