Peripheral interactions between cannabinoid and opioid receptor agonists in a model of inflammatory mechanical hyperalgesia.
Peripheral interactions between cannabinoid and opioid receptor agonists in a model of inflammatory mechanical hyperalgesia.
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DOI：
10.1016/j.brainresbull.2016.07.009
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发表时间：
2016-07
影响因子：
3.8
通讯作者：
Ro JY
中科院分区：
文献类型：
--
作者：
Auh QS;Chun YH;Melemedjian OK;Zhang Y;Ro JY
在伤害性感受器中表达的阿片和大麻素受体的激活可以诱导有效的止痛。在这项研究中，我们研究了针对损伤部位的阿片和大麻受体激动剂的组合是否会提高治疗效果。通过行为药理学实验，比较μ阿片受体选择性激动剂DAMGO、CB1特异性激动剂ACPA以及两者合用对完全弗氏佐剂所致大鼠后足机械性痛敏的影响。在机械性痛觉过敏完全形成后，将丹参酮(1μg~(-1)mg)或乙酰丙酸(1μg~(-2)mg)注入致炎大鼠的爪部。单独给药时，DAMGO和ACPA可剂量依赖性地逆转机械性痛敏。DAMGO的ED50值(57.4±2.49μg)低于ACPA(111.6±2.18μg)，但ACPA具有更持久的止痛作用。DAMGO和ACPA联合应用也可剂量依赖性地减轻机械性痛敏，但即使在高剂量下，其止痛作用也是部分的和短暂的。结果表明，丹参和乙酰丙酸联合给药有拮抗作用，其ED_(50)为128.4±2.28μg。结果表明，单独给药时，MOR和Cb1激动剂能有效地减轻机械性痛觉过敏，而合用时则相反。这两类药物在炎症部位的拮抗作用表明，外周伤害性感受器或炎症组织具有独特的机制，因此需要进一步研究，以探索联合药物治疗在慢性疼痛条件下的治疗效用是否可以优化。
Activation of opioid and cannabinoid receptors expressed in nociceptors induces effective antihyperalgesia. In this study, we examined whether combinations of opioid and cannabinoid receptor agonists directed at the injured site would enhance therapeutic effectiveness. Behavioral pharmacology experiments were performed to compare the effects of DAMGO, a selective agonist for μ-opioid receptor (MOR), ACPA, a specific agonist for CB1, and combinations of DAMGO and ACPA in attenuating complete Freund’s adjuvant (CFA)-induced mechanical hyperalgesia in the rat hindpaw. DAMGO (1 μg–1 mg) or ACPA (1 μg–2 mg) was administered into the inflamed paw when mechanical hyperalgesia was fully developed. When administered individually, DAMGO and ACPA dose-dependently reversed the mechanical hyperalgesia. DAMGO displayed a lower ED50 value (57.4 ± 2.49 μg) than ACPA (111.6 ± 2.18 μg), but ACPA produced longer lasting antihyperalgesic effects. Combinations of DAMGO and ACPA also dose-dependently attenuated mechanical hyperalgesia, but the antihyperalgesic effects were partial and transient even at high doses. Using isobolographic analysis, we determined that combined treatment with DAMGO and ACPA produced antagonistic effects with the observed ED50 of 128.4 ± 2.28 μg. Our findings showed that MOR and CB1 agonists directed at the inflamed site effectively attenuate mechanical hyperalgesia when administered individually, but exert opposing effects when administered together. The antagonistic interactions between the two classes of drugs at the inflamed site suggest distinct mechanisms unique to peripheral nociceptors or inflamed tissue, and therefore require further studies to investigate whether the therapeutic utility of the combined drug treatments in chronic pain conditions can be optimized.
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