Raghavendra Vasudeva, Tanga Flobert, Rutkowski Maria D, DeLeo Joyce A
Department of Anesthesiology, HB 7125, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756, USA Department of Pharmacology, HB 7125, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756, USA.
Pain. 2003 Aug;104(3):655-664. doi: 10.1016/S0304-3959(03)00138-6.
Injury to peripheral nerves often produces non-physiological, long-lasting spontaneous pain, hyperalgesia and allodynia that are refractory to standard treatment and often insensitive to opioids, such as morphine. Recent studies demonstrate spinal glial activation and increased proinflammatory cytokines in animal models of neuropathic pain. When these data are considered together, a unifying hypothesis emerges which implicates a role of central neuroimmune processes in the etiology of neuronal and behavioral hypersensitivity. The present investigation assessed the influence of propentofylline, a glial modulating and anti-inflammatory agent, on the development of L5 spinal nerve transection-induced hyperalgesia and associated enhancement of spinal neuroimmune responses using real-time reverse transcription-polymerase chain reaction, RNase protection assay, enzyme-linked immunosorbent assay, and immunocytochemistry in rats. The results show that chronic propentofylline treatment attenuated the development of hyperalgesia and restored the analgesic activity of acute morphine in neuropathic rats. These findings directly correlated with the ability of propentofylline to inhibit glial activation and enhanced spinal proinflammatory cytokines following peripheral nerve injury. These findings along with our earlier observations of an anti-allodynic activity of propentofylline using the identical animal model of mononeuropathy supports the concept that modulation of glial and neuroimmune activation may be potential therapeutic targets to treat or prevent neuropathic pain. Further, restoration of the analgesic activity of morphine by propentofylline treatment suggests that increased glial activity and proinflammatory cytokine responses may account for the decreased analgesic efficacy of morphine observed in the treatment of neuropathic pain.
外周神经损伤常产生非生理性的、持续时间长的自发痛、痛觉过敏和异常性疼痛，这些症状对标准治疗无效，且通常对吗啡等阿片类药物不敏感。最近的研究表明，在神经性疼痛的动物模型中，脊髓胶质细胞激活，促炎细胞因子增加。综合考虑这些数据，一个统一的假说出现了，即中枢神经免疫过程在神经元和行为超敏反应的病因中起作用。本研究使用实时逆转录聚合酶链反应、核糖核酸酶保护分析、酶联免疫吸附测定和免疫细胞化学，评估了一种胶质细胞调节和抗炎药物丙戊茶碱对L5脊髓神经横断诱导的痛觉过敏的发展以及脊髓神经免疫反应相关增强的影响。结果表明，慢性丙戊茶碱治疗减轻了痛觉过敏的发展，并恢复了急性吗啡在神经性大鼠中的镇痛活性。这些发现与丙戊茶碱抑制外周神经损伤后胶质细胞激活和增强脊髓促炎细胞因子的能力直接相关。这些发现以及我们早期使用相同单神经病动物模型观察到的丙戊茶碱的抗异常性疼痛活性，支持了调节胶质细胞和神经免疫激活可能是治疗或预防神经性疼痛的潜在治疗靶点这一概念。此外，丙戊茶碱治疗恢复了吗啡的镇痛活性，这表明胶质细胞活性增加和促炎细胞因子反应可能是神经性疼痛治疗中观察到的吗啡镇痛效果降低的原因。
