反复使用吗啡会延长雄性大鼠的术后疼痛。
Repeated Morphine Prolongs Postoperative Pain in Male Rats.
机构信息
From the Department of Psychology and Neuroscience, and The Center for Neuroscience, University of Colorado, Boulder, Colorado.
Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
出版信息
Anesth Analg. 2019 Jan;128(1):161-167. doi: 10.1213/ANE.0000000000003345.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
背景
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外周和中枢神经性疼痛。这些有害影响是由免疫介质介导的，这些免疫介质促进脊髓背角神经元过度兴奋。在此，我们测试了围手术期吗啡是否也会导致雄性大鼠的术后疼痛延长。
方法
吗啡处理组大鼠在剖腹手术后立即接受吗啡治疗，持续 7 天，而在第二组中逐渐减少吗啡剂量。在脊髓背角中定量检测炎症介质的基因表达。在最后的实验中，吗啡在术前 7 天进行给药。
结果
我们发现，手术后给予吗啡治疗会使术后疼痛延长超过 3 周（时间×处理：P<0.001；时间：P<0.001；处理：P<0.05）。术后疼痛的延长与吗啡戒断无关，因为逐渐减少剂量并不能预防（时间×处理：P=0.8；时间：P<0.001；处理：P=0.9）。术后慢性疼痛与炎症基因表达增加有关，包括编码 Toll 样受体 4、NOD 样受体蛋白 3（NLRP3）、核因子 kappa B（NFκB）、半胱天冬酶-1、白细胞介素-1β和肿瘤坏死因子（P<0.05）。最后，我们发现术前吗啡治疗，即在剖腹手术前立即结束，同样会延长术后疼痛（时间×处理：P<0.001；时间：P<0.001；处理：P<0.001）。吗啡增强疼痛存在一个关键窗口，因为在剖腹手术前 1 周结束的 7 天吗啡疗程不会延长术后疼痛。
结论
这些研究表明吗啡可能对术后疼痛产生有害影响。这些研究进一步表明，可以进行纵向研究来测试阿片类药物是否在临床上也会延长术后疼痛。
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