Zhang Xin, Wang Jing, Yu Tingting, Du Dongping, Jiang Wei
Pain Management Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Clin Exp Pharmacol Physiol. 2015 Jan;42(1):94-101. doi: 10.1111/1440-1681.12316.
Neuropathic pain is a challenge for physicians and basic science researchers, because it often does not respond to routine treatment. The administration of morphine has been considered one of the effective recommended treatments, but its wide application is limited because of the development of antinociceptive tolerance. In general, basic science studies focus on neuropathic pain and morphine tolerance separately. However, we tried to investigate the effect of microglial activation on morphine tolerance in spinal nerve ligation (SNL) rats during the maintenance period of neuropathic pain. This study produced the following results. The morphine tolerance model in neuropathic pain was established by repeated administration of morphine twice daily (10 mg/kg s.c) in the maintenance period of SNL rats. Minocycline, the microglial activation inhibitor, was given once daily (30 mg/kg, i.p.) at different time-points. The CD11b protein level was measured by western blot to monitor microglial activation. Rats' mechanical allodynia was assessed using the 50% paw withdrawal threshold, and the tail antinociception was determined using the percentage of the maximal possible antinociceptive effect. First, the repeated administration of morphine induced the development of antinociceptive tolerance during the maintenance period of neuropathic pain. Second, during the development of morphine tolerance, microglial activation, which is related to the analgesic effect of morphine, decreased in the first few days, but this pattern was reversed in the following days with the development of morphine tolerance. Third, the repeated administration of minocycline, a microglial activation inhibitor, did not influence the antinociceptive effect of a single dose of morphine. Fourth, the pre-administration of minocycline can delay the development of morphine tolerance, but repeated minocycline administration cannot reverse existing morphine tolerance. We concluded that microglial activation contributes to the morphine tolerance of SNL rats in the maintenance period of neuropathic pain, and that minocycline delays the development of morphine tolerance, but does not reverse existing morphine tolerance during the maintenance period of neuropathic pain in rats. These findings might be useful for clinical pain management.
神经病理性疼痛对医生和基础科学研究人员来说都是一项挑战，因为它通常对常规治疗没有反应。吗啡给药一直被认为是有效的推荐治疗方法之一，但其广泛应用受到抗伤害感受性耐受发展的限制。一般来说，基础科学研究分别关注神经病理性疼痛和吗啡耐受。然而，我们试图研究在神经病理性疼痛维持期，脊髓神经结扎（SNL）大鼠中，小胶质细胞激活对吗啡耐受的影响。本研究得出了以下结果。在SNL大鼠的维持期，通过每日两次重复给予吗啡（10mg/kg，皮下注射）建立神经病理性疼痛中的吗啡耐受模型。小胶质细胞激活抑制剂米诺环素在不同时间点每日一次（30mg/kg，腹腔注射）给药。通过蛋白质免疫印迹法测量CD11b蛋白水平以监测小胶质细胞激活。使用50%爪部撤离阈值评估大鼠的机械性异常性疼痛，并使用最大可能抗伤害感受效应的百分比确定尾部抗伤害感受。首先，重复给予吗啡在神经病理性疼痛维持期诱导了抗伤害感受性耐受的发展。其次，在吗啡耐受发展过程中，与吗啡镇痛作用相关的小胶质细胞激活在最初几天减少，但随着吗啡耐受的发展，这种模式在随后几天发生了逆转。第三，重复给予小胶质细胞激活抑制剂米诺环素不影响单剂量吗啡的抗伤害感受作用。第四，预先给予米诺环素可延迟吗啡耐受的发展，但重复给予米诺环素不能逆转现有的吗啡耐受。我们得出结论，在神经病理性疼痛维持期，小胶质细胞激活促成了SNL大鼠的吗啡耐受，并且米诺环素可延迟吗啡耐受的发展，但在大鼠神经病理性疼痛维持期不能逆转现有的吗啡耐受。这些发现可能对临床疼痛管理有用。
