Hurley R W, Hammond D L
Department of Anesthesia and Critical Care and The Committee on Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.
J Neurosci. 2001 Apr 1;21(7):2536-45. doi: 10.1523/JNEUROSCI.21-07-02536.2001.
This study examined a mechanism responsible for the enhanced antihyperalgesic and antinociceptive effects of the mu opioid receptor agonist (ORA) [D-Ala(2), NMePhe(4), Gly(5)-ol]enkephalin (DAMGO) microinjected in the rostroventromedial medulla (RVM) of rats with inflammatory injury induced by injection of complete Freund's adjuvant (CFA) in one hindpaw. In rats injected with CFA 4 hr earlier, microinjection of the mu opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) in the RVM antagonized both the marginal enhancement of the potency of DAMGO and its antinociceptive effect. The delta opioid receptor antagonist naltriben (NTB) was without effect. In rats injected with CFA 2 weeks earlier, CTAP antagonized the effects of DAMGO to a lesser extent. However, NTB completely prevented the enhancement of the potency of DAMGO, whereas it did not antagonize DAMGO's antinociceptive effects. Microinjection of NTB alone, but not CTAP in the RVM of CFA-treated rats, enhanced the hyperalgesia present in the ipsilateral hindpaw and induced hyperalgesia in the contralateral, uninjured hindpaw. These results suggest that persistent inflammatory injury increased the release in the RVM of opioid peptides with preferential affinity for the delta opioid receptor, which can interact in a synergistic or additive manner with an exogenously administered mu opioid receptor agonist. Indeed, the levels of [Met(5)]enkephalin and [Leu(5)]enkephalin were increased in the RVM and in other brainstem nuclei in CFA-treated rats. This increase most likely presents a compensatory neuronal response of the CNS of the injured animal to mitigate the full expression of inflammatory pain and to enhance the antinociceptive and antihyperalgesic effects of exogenously administered mu opioid receptor analgesics.
本研究考察了一种机制，该机制负责增强μ阿片受体激动剂（ORA）[D-丙氨酸（2），N-甲基苯丙氨酸（4），甘氨酸（5）-醇]脑啡肽（DAMGO）微量注射于一侧后爪注射完全弗氏佐剂（CFA）诱导炎症损伤大鼠的延髓头端腹内侧区（RVM）时的抗痛觉过敏和镇痛作用。在4小时前注射CFA的大鼠中，在RVM微量注射μ阿片受体拮抗剂D-苯丙氨酸-半胱氨酸-酪氨酸-D-色氨酸-精氨酸-苏氨酸-苯丙氨酸-苏氨酸-NH₂（CTAP）可拮抗DAMGO效力的边缘增强及其镇痛作用。δ阿片受体拮抗剂纳曲苄（NTB）则无此作用。在2周前注射CFA的大鼠中，CTAP对DAMGO作用的拮抗程度较小。然而，NTB完全阻断了DAMGO效力的增强，而未拮抗DAMGO的镇痛作用。在CFA处理大鼠的RVM中单独微量注射NTB而非CTAP，可增强同侧后爪的痛觉过敏，并在对侧未受伤后爪诱导痛觉过敏。这些结果表明，持续性炎症损伤增加了对δ阿片受体具有优先亲和力的阿片肽在RVM中的释放，其可与外源性给予的μ阿片受体激动剂以协同或相加方式相互作用。实际上，在CFA处理大鼠的RVM和其他脑干核团中，[甲硫氨酸（5）]脑啡肽和[亮氨酸（5）]脑啡肽水平升高。这种升高很可能是受伤动物中枢神经系统的一种代偿性神经元反应，以减轻炎症性疼痛的充分表达，并增强外源性给予的μ阿片受体镇痛药的镇痛和抗痛觉过敏作用。
