Morgan Michael M, Reid Rachel A, Stormann Thomas M, Lautermilch Nathan J
Department of Psychology, Washington State University Vancouver, Vancouver, Washington.
Department of Psychology, Washington State University Vancouver, Vancouver, Washington.
J Pain. 2014 Nov;15(11):1102-1109. doi: 10.1016/j.jpain.2014.07.008. Epub 2014 Aug 5.
Morphine and fentanyl produce antinociception in part by binding to mu-opioid receptors in the periaqueductal gray (PAG). The present study tested the hypothesis that the PAG also contributes to the antinociceptive effects of other commonly used opioids (oxycodone, methadone, and buprenorphine). Microinjection of high doses of oxycodone (32-188 μg/.4 μL) into the ventrolateral PAG of the rat produced a dose-dependent increase in hot plate latency. This antinociception was evident within 5 minutes and nearly gone by 30 minutes. In contrast, no antinociception was evident following microinjection of methadone or buprenorphine into the ventrolateral PAG despite use of a wide range of doses and test times. Antinociception was evident following subsequent microinjection of morphine into the same injection sites or following systemic administration of buprenorphine, demonstrating that the injections sites and drugs could support antinociception. Antinociception to systemic, but not PAG, administration of buprenorphine occurred in both male and female rats. These and previous data demonstrate that the mu-opioid receptor signaling pathway for antinociception in the PAG is selectively activated by some commonly used opioids (eg, morphine, fentanyl, and oxycodone) but not others (eg, methadone or buprenorphine). The fact that methadone and buprenorphine produce antinociception following systemic administration demonstrates that mu-opioid receptor signaling varies depending on location in the nervous system.
This study demonstrates that the PAG contributes to the antinociceptive effects of some commonly used opioids (morphine, fentanyl, and oxycodone) but not others (methadone or buprenorphine). Such functional selectivity in PAG-mediated opioid antinociception helps explain why the analgesic profile of opioids is so variable.
吗啡和芬太尼部分通过与中脑导水管周围灰质（PAG）中的μ-阿片受体结合产生抗伤害感受作用。本研究检验了以下假设：PAG也有助于其他常用阿片类药物（羟考酮、美沙酮和丁丙诺啡）的抗伤害感受作用。向大鼠腹外侧PAG微量注射高剂量的羟考酮（32 - 188μg/.4μL）会使热板潜伏期呈剂量依赖性增加。这种抗伤害感受作用在5分钟内明显，30分钟时几乎消失。相比之下，尽管使用了广泛的剂量范围和测试时间，向腹外侧PAG微量注射美沙酮或丁丙诺啡后未观察到明显的抗伤害感受作用。在相同注射部位随后微量注射吗啡或全身给予丁丙诺啡后出现了抗伤害感受作用，表明注射部位和药物能够产生抗伤害感受作用。丁丙诺啡全身给药而非PAG给药在雄性和雌性大鼠中均产生了抗伤害感受作用。这些数据以及之前的数据表明，PAG中抗伤害感受的μ-阿片受体信号通路被一些常用阿片类药物（如吗啡、芬太尼和羟考酮）选择性激活，而不是其他药物（如美沙酮或丁丙诺啡）。美沙酮和丁丙诺啡全身给药后产生抗伤害感受作用这一事实表明，μ-阿片受体信号传导因在神经系统中的位置而异。
本研究表明，PAG有助于一些常用阿片类药物（吗啡、芬太尼和羟考酮）的抗伤害感受作用，但对其他药物（美沙酮或丁丙诺啡）则不然。PAG介导的阿片类药物抗伤害感受中的这种功能选择性有助于解释为什么阿片类药物的镇痛谱如此多变。
