Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation.
Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation.
复制标题
DOI：
10.1038/tp.2014.121
复制
发表时间：
2014-11-11
影响因子：
6.8
通讯作者：
Hutchinson MR
中科院分区：
文献类型：
--
作者：
Johnson JL;Rolan PE;Johnson ME;Bobrovskaya L;Williams DB;Johnson K;Tuke J;Hutchinson MR
慢性吗啡治疗与矛盾的疼痛增加有关。可待因是一种广泛使用的阿片类药物，它被代谢成吗啡来产生镇痛作用。长期接触吗啡会激活中枢神经系统中的天然免疫Toll样受体-4(TLR4)，从而加剧疼痛。在电子对接模拟中，可待因也与TLR4的辅助蛋白MD2对接，这表明有可能诱导TLR4依赖的疼痛易化。我们假设可待因会导致依赖TLR4的痛觉过敏/痛觉异常，这与其阿片受体依赖的止痛药等级效力不同。分别于第0、3、5天分别给予等摩尔可待因(21 mg kg−1)、吗啡(20 mg kg−1)或生理盐水灌胃，分别于第0、3、5天用热板法和von Frey法检测痛觉过敏和痛觉过敏反应。这项实验在既往部分神经损伤的动物和TLR4缺失突变小鼠身上重复进行。对白细胞介素1受体拮抗剂(IL-1RA)和胶质细胞减弱剂异丁司特的干预效果进行评估。在行为学测试结束时，对神经元组织中的胶质细胞活化标志物(胶质纤维酸性蛋白和CD11b)进行分析。尽管可待因的急性镇痛作用较弱(P=0.006)，但可待因引起的热板痛敏与等摩尔吗啡与生理盐水相似(分别为−9.5 S，P<；0.01和−7.3 S，P<；0.01)，表明可待因不依赖于转化为吗啡来增加疼痛敏感性。这突出了可待因增强疼痛敏感性的潜在的非阿片受体依赖的性质--尽管不能排除其他可待因代谢物的参与。IL-1RA逆转可待因引起的痛觉过敏(P<；0.001)和超敏(P<；0.001)，TLR4基因敲除对可待因引起的疼痛敏感性的改变有保护作用。异丁司特可逆转可待因诱导的痛觉异常(P<；0.001)，因此可以进一步研究可待因诱导的疼痛增强的潜在治疗方法。
Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg−1), morphine (20 mg kg−1) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 null mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (−9.5 s, P<0.01 and −7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity—although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.
登录
查看更多内容
影响因子：
15.1
作者：
Hutchinson, Mark R.;Zhang, Yingning;Shridhar, Mitesh;Evans, John H.;Buchanan, Madison M.;Zhao, Tina X.;Slivka, Peter F.;Coats, Benjamen D.;Rezvani, Niloofar;Wieseler, Julie;Hughes, Travis S.;Landgraf, Kyle E.;Chan, Stefanie;Fong, Stephanie;Phipps, Simon;Falke, Joseph J.;Leinwand, Leslie A.;Maier, Steven F.;Yin, Hang;Rice, Kenner C.;Watkins, Linda R.
通讯作者：
Watkins, Linda R.
影响因子：
6.3
作者：
Clark, Simon R.;McMahon, Catherine J.;Rothwell, Nancy J.
通讯作者：
Rothwell, Nancy J.
影响因子：
3
作者：
Grace, Peter M.;Hutchinson, Mark R.;Rolan, Paul E.
通讯作者：
Rolan, Paul E.
影响因子：
3.6
作者：
Hamunen, Katri;Laitinen-Parkkonen, Pirjo;Kalso, Eija
通讯作者：
Kalso, Eija
影响因子：
8.8
作者：
Célèrier, E;Rivat, C;Simonnet, G
通讯作者：
Simonnet, G