Bileviciute-Ljungar Indre, Spetea Mariana, Guo Yan, Schütz Johannes, Windisch Petra, Schmidhammer Helmut
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
J Pharmacol Exp Ther. 2006 Apr;317(1):220-7. doi: 10.1124/jpet.105.096032. Epub 2005 Dec 8.
Opioids induce analgesia by activating opioid receptors not only within the central nervous system but also on peripheral sensory neurons. This study investigated peripherally mediated antinociception produced by the mu-opioid receptor agonist 2-[(4,5alpha-epoxy-3-hydroxy-14beta-methoxy-17-methylmorphinan-6beta-yl)amino]acetic acid (HS-731) after s.c. and oral administration in rats with carrageenan-induced hindpaw inflammation. Antinociceptive effects after s.c. administration were assessed 3 h after intraplantar carrageenan injection and compared with those of centrally acting mu-opioid agonists 14-methoxymetopon and morphine. Opioid agonists caused dose-dependent increases in inflamed paw withdrawal latencies to mechanical and thermal stimulation. The time course of action was different, in that HS-731 (20 microg/kg s.c.) produced significant long-lasting effects up to 4 h after administration, whereas 14-methoxymetopon (20 microg/kg) and morphine (2 mg/kg) reached their peak of action at 10 to 30 min, and their effect declined rapidly thereafter. Subcutaneous administration of the peripherally selective opioid antagonist naloxone methiodide inhibited antinociception elicited by HS-731 (20 microg/kg s.c.), whereas it was ineffective against 14-methoxymetopon (20 microg/kg s.c.). Moreover, the antinociception produced by 100 microg/kg s.c. HS-731 was dose-dependently reversed by s.c. naloxone methiodide. This indicates that HS-731 preferentially activates peripheral opioid receptors, whereas 14-methoxymetopon mediates analgesia via central mechanisms. Orally administered HS-731 significantly reduced hyperalgesia in the inflamed paw induced by carrageenan, which was reversible by s.c. administered naloxone methiodide. These results show that systemic (s.c. and oral) treatment with the mu-opioid agonist HS-731 produces potent and long-lasting antinociception through peripheral mechanisms in rats with carrageenan-induced hindpaw inflammation.
阿片类药物不仅通过激活中枢神经系统内的阿片受体，还通过激活外周感觉神经元上的阿片受体来诱导镇痛。本研究调查了在角叉菜胶诱导后爪炎症的大鼠中，μ-阿片受体激动剂2-[(4,5α-环氧-3-羟基-14β-甲氧基-17-甲基吗啡喃-6β-基)氨基]乙酸（HS-731）皮下和口服给药后产生的外周介导的抗伤害感受作用。在足底注射角叉菜胶3小时后评估皮下给药后的抗伤害感受作用，并与中枢作用的μ-阿片激动剂14-甲氧基美托酮和吗啡的抗伤害感受作用进行比较。阿片激动剂使炎症后爪对机械和热刺激的撤爪潜伏期呈剂量依赖性增加。作用的时间过程不同，因为HS-731（20微克/千克皮下注射）在给药后长达4小时产生显著的持久作用，而14-甲氧基美托酮（20微克/千克）和吗啡（2毫克/千克）在10至30分钟达到作用峰值，此后其作用迅速下降。皮下注射外周选择性阿片拮抗剂甲硫氧吗啡酮可抑制HS-731（20微克/千克皮下注射）引起的抗伤害感受，而对14-甲氧基美托酮（20微克/千克皮下注射）无效。此外，皮下注射甲硫氧吗啡酮可剂量依赖性地逆转100微克/千克皮下注射HS-731产生的抗伤害感受。这表明HS-731优先激活外周阿片受体，而14-甲氧基美托酮通过中枢机制介导镇痛。口服HS-731可显著减轻角叉菜胶诱导的炎症后爪的痛觉过敏，皮下注射甲硫氧吗啡酮可使其逆转。这些结果表明，在角叉菜胶诱导后爪炎症的大鼠中，用μ-阿片激动剂HS-731进行全身（皮下和口服）治疗可通过外周机制产生强效且持久的抗伤害感受作用。
