Nwaneshiudu Chinwe, Shi Xiao-Yu, Sahbaie Peyman, David Clark J
Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
Veterans Affairs Palo Alto Healthcare System, Anesthesiology Service, Palo Alto, CA, USA.
Mol Pain. 2021 Jan-Dec;17:1744806920988443. doi: 10.1177/1744806920988443.
Recent reports suggest pain from surgical injury may influence the risks associated with exposure to opioids. In mice, hind-paw incision attenuates morphine-primed reinstatement due to kappa opioid receptor activation by dynorphin. In this focused group of studies, we examined the hypotheses that kappa-opioid receptor activation in the nucleus accumbens mediates attenuated drug- primed reinstatement after incisional surgery, and the G-protein biased mu-opioid agonist, oliceridine, leads to less priming of the dynorphin effect in comparison to morphine. To address these hypotheses, adult C57BL/6 male mice underwent intracranial cannulation for administration of the selective kappa-opioid antagonist norBNI directly into the nucleus accumbens. After recovery, they were conditioned with morphine or oliceridine after hind-paw incisional injury, then underwent extinction followed by opioid-primed reinstatement. Intra-accumbal administration of norBNI was carried out prior to testing. The nucleus accumbens and medial prefrontal cortex were extracted and analyzed for expression of prodynorphin. We observed that animals conditioned with morphine in the setting of incisional injury demonstrated blunted responses to opioid-primed reinstatement, and that the blunted responses were reversed with intra-accumbal norBNI administration. Persistently elevated levels of prodynorphin expression in the medial prefrontal cortex and nucleus accumbens were observed in the incised morphine-treated animals. However, both behavioral and molecular changes were absent in animals with incisional injury conditioned with oliceridine. These findings suggest a role for prodynorphin expression in the nucleus accumbens with exposure to morphine after surgery that may protect individuals from relapse not shared with biased mu- opioid receptor agonists.
近期报告表明，手术损伤带来的疼痛可能会影响与接触阿片类药物相关的风险。在小鼠中，后爪切开术会减弱因强啡肽激活κ阿片受体而导致的吗啡引发的复吸行为。在这组重点研究中，我们检验了以下假设：伏隔核中的κ阿片受体激活介导了切开手术后药物引发的复吸行为减弱，并且与吗啡相比，G蛋白偏向性μ阿片受体激动剂奥利替丁对强啡肽效应的引发作用较小。为了验证这些假设，成年C57BL/6雄性小鼠接受颅内插管，以便将选择性κ阿片拮抗剂norBNI直接注入伏隔核。恢复后，它们在后爪切开损伤后用吗啡或奥利替丁进行条件化训练，然后进行消退训练，随后进行阿片类药物引发的复吸测试。在测试前进行伏隔核内注射norBNI。提取伏隔核和内侧前额叶皮质并分析前强啡肽的表达。我们观察到，在切开损伤情况下用吗啡进行条件化训练的动物对阿片类药物引发的复吸表现出钝化反应，而通过伏隔核内注射norBNI可逆转这种钝化反应。在切开后用吗啡治疗的动物中，观察到内侧前额叶皮质和伏隔核中前强啡肽表达持续升高。然而，在切开损伤并用奥利替丁进行条件化训练的动物中，行为和分子变化均未出现。这些发现表明，手术后接触吗啡时，伏隔核中前强啡肽的表达可能发挥作用，保护个体免于复发，而这一作用在偏向性μ阿片受体激动剂中并不存在。
