Berg Kelly A, Patwardhan Amol M, Sanchez Teresa A, Silva Yamille M, Hargreaves Kenneth M, Clarke William P
Department of Pharmacology, MS 7764, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
J Pharmacol Exp Ther. 2007 Jun;321(3):839-47. doi: 10.1124/jpet.106.116681. Epub 2007 Mar 8.
Management of pain by opioid analgesics is confounded by central adverse effects that limit clinical dosages. Consequently, there is considerable interest to understand peripheral analgesic effects of opioids. The actions of opioids on peripheral sensory neurons have been difficult to study because of a general lack of effect of opioid agonists on nociceptor function in culture despite documented presence of opioid receptors. In this study, the micro-opioid receptor agonist, [D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin (DAMGO), did not alter guanosine 5'-O-(3-[(35)S]thio)-triphosphate (GTPgamma[(35)S]) binding, adenylyl cyclase activity, or neuropeptide release in primary cultures of rat trigeminal ganglion (TG). However, after brief exposure to bradykinin (BK), DAMGO stimulated GTPgamma[(35)S] binding and inhibited both prostaglandin E(2) (PGE(2))-stimulated adenylyl cyclase activity and BK/PGE(2)-stimulated neuropeptide release. The effect of BK was blocked by the B(2) antagonist HOE 140 [D-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-bradykinin], but not by the B(1) antagonist, Lys-[Leu8]des-Arg9-BK, and was mimicked by the protease-activated receptor-2 agonist, Ser-Leu-Ile-Gly-Arg-Leu-NH(2), and by activation of protein kinase C (PKC) or by administration of arachidonic acid (AA). The enhanced responsiveness of micro-opioid receptor signaling by BK priming was blocked by both cyclooxygenase and PKC inhibitors; however, the effect of AA was blocked only by a cyclooxygenase inhibitor. The results indicate that micro-opioid receptor signaling in primary sensory TG neurons is enhanced by activation of phospholipase C-coupled receptors via a cyclooxygenase-dependent AA metabolite that is downstream of PKC.
阿片类镇痛药对疼痛的管理因中枢不良反应而受到困扰，这些不良反应限制了临床剂量。因此，人们对了解阿片类药物的外周镇痛作用有着浓厚的兴趣。由于尽管有文献记载阿片受体的存在，但阿片类激动剂对培养中的伤害感受器功能普遍缺乏作用，因此研究阿片类药物对周围感觉神经元的作用一直很困难。在本研究中，微阿片受体激动剂[D-Ala(2),N-MePhe(4),Gly-ol(5)]-脑啡肽（DAMGO）并未改变大鼠三叉神经节（TG）原代培养物中鸟苷5'-O-(3-[(35)S]硫代)-三磷酸（GTPγ[(35)S]）结合、腺苷酸环化酶活性或神经肽释放。然而，在短暂暴露于缓激肽（BK）后，DAMGO刺激了GTPγ[(35)S]结合，并抑制了前列腺素E2（PGE2）刺激的腺苷酸环化酶活性以及BK/PGE2刺激的神经肽释放。BK的作用被B(2)拮抗剂HOE 140 [D-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-缓激肽]阻断，但未被B(1)拮抗剂Lys-[Leu8]des-Arg9-BK阻断，并且被蛋白酶激活受体-2激动剂Ser-Leu-Ile-Gly-Arg-Leu-NH2、蛋白激酶C（PKC）的激活或花生四烯酸（AA）的给药所模拟。BK引发对微阿片受体信号传导的增强反应性被环氧化酶和PKC抑制剂均阻断；然而，AA的作用仅被环氧化酶抑制剂阻断。结果表明，通过磷脂酶C偶联受体的激活，经由PKC下游的环氧化酶依赖性AA代谢产物，原代感觉TG神经元中的微阿片受体信号传导得到增强。
