Repeated Morphine Prolongs Postoperative Pain in Male Rats.
Repeated Morphine Prolongs Postoperative Pain in Male Rats.
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DOI：
10.1213/ane.0000000000003345
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发表时间：
2019-01
影响因子：
5.7
通讯作者：
Watkins LR
中科院分区：
文献类型：
--
作者：
Grace PM;Galer EL;Strand KA;Corrigan K;Berkelhammer D;Maier SF;Watkins LR
阿片类药物是有效的术后镇痛剂。令人不安的是，我们之前曾报道过吗啡等阿片类药物会加重炎症性疼痛以及周围和中枢神经性疼痛。这些有害的影响是由促进脊髓背角神经元过度兴奋的免疫介质介导的。在这里，我们测试了围手术期吗啡是否同样可以延长雄性大鼠的术后疼痛。大鼠接受7天的吗啡治疗，从剖腹手术后立即开始，而第二组则逐渐减少吗啡。炎性介质基因在脊髓背角中的表达被量化。在最后一次实验中，在开腹前注射吗啡，持续7天。我们发现，开腹手术后吗啡治疗延长术后疼痛超过3周(时间×治疗：P<；.001；时间：P<；.001；治疗：P<；.05)。术后疼痛的延长与吗啡戒断无关，因为它不能通过剂量缩减来预防(时间×治疗：P=.8；时间：P<；.001；治疗：P=.9)。术后较长时间的疼痛与炎症基因的表达增加有关，包括编码Toll样受体4、结节样受体蛋白3(NLRP3)、核因子kappaB(NFκB)、半胱氨酸天冬氨酸氨基转移酶-1(caspase-1)、白介素1β和肿瘤坏死因子(P<；0.05)。最后，我们展示了术前吗啡同样延长了术后疼痛(时间×治疗：P<；.001；时间：P<；.001；治疗：P<；.001)。吗啡增强疼痛有一个关键的窗口，因为在开腹手术前1周结束的7天吗啡疗程并没有延长手术后的疼痛。这些研究表明，吗啡对术后疼痛有有害影响。这些研究进一步表明，可以进行纵向研究，以测试阿片类药物是否同样延长了临床上的术后疼痛。
Opioids are effective postoperative analgesics. Disturbingly, we have previously reported that opioids such as morphine can worsen inflammatory pain and peripheral and central neuropathic pain. These deleterious effects are mediated by immune mediators that promote neuronal hyperexcitability in the spinal dorsal horn. Herein, we tested whether perioperative morphine could similarly prolong postoperative pain in male rats. Rats were treated with morphine for 7 days, beginning immediately after laparotomy, while the morphine was tapered in a second group. Expression of genes for inflammatory mediators was quantified in the spinal dorsal horn. In the final experiment, morphine was administered before laparotomy for 7 days. We found that morphine treatment after laparotomy extended postoperative pain by more than 3 weeks (time × treatment: P < .001; time: P < .001; treatment: P < .05). Extension of postoperative pain was not related to morphine withdrawal, as it was not prevented by dose tapering (time × treatment: P = .8; time: P < .001; treatment: P = .9). Prolonged postsurgical pain was associated with increased expression of inflammatory genes, including those encoding Toll-like receptor 4, NOD like receptor protein 3 (NLRP3), nuclear factor kappa B (NFκB), caspase-1, interleukin-1β, and tumor necrosis factor (P < .05). Finally, we showed that of preoperative morphine, concluding immediately before laparotomy, similarly prolonged postoperative pain (time × treatment: P < .001; time: P < .001; treatment: P < .001). There is a critical window for morphine potentiation of pain, as a 7-day course of morphine that concluded 1 week before laparotomy did not prolong postsurgical pain. These studies indicate the morphine can have a deleterious effect on postoperative pain. These studies further suggest that longitudinal studies could be performed to test whether opioids similarly prolong postoperative pain in the clinic.