The present study was performed to determine neuronal loci and individual molecular mechanisms responsible for remifentanil-induced hyperalgesia. The effect of methylnaltrexone (MNX) on remifentanil-induced behavioral hyperalgesia was assessed to distinguish contributions of the peripheral and/or central nervous system to remifentanil-induced hyperalgesia. Phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) in the dorsal root ganglion (DRG) neurons after remifentanil infusion, and the effect of a p38MAPK inhibitor on remifentanil-induced hyperalgesia were analyzed to investigate involvement of p38MAPK in the peripheral mechanisms of remifentanil-induced hyperalgesia. Spinal levels of prodynorphin mRNA after remifentanil infusion, and the effect of the BK2 bradykinin receptor antagonist on remifentanil-induced hyperalgesia were investigated to assess potential spinal mechanisms. The effects of MNX and BK2 antagonists on remifentanil-induced exacerbation of post-incisional hyperalgesia were also investigated using behavioral analysis. Remifentanil infusion induced hyperalgesia in the early (4 h to 2 days) and late (8–14 days) post-infusion periods. MNX inhibited hyperalgesia only during the early post-infusion period. p38MAPK phosphorylation was observed in the DRG neuron, and the p38MAPK inhibitor inhibited hyperalgesia during the early post-infusion period. Prodynorphin expression increased in the spinal cord, and a BK2 antagonist inhibited hyperalgesia during the late post-infusion period. Remifentanil-induced exacerbation of incisional hyperalgesia was inhibited by MNX and the BK2 antagonist. The present study demonstrated that remifentanil activates peripheral and spinal neurons to promote chronologically distinctive hyperalgesia. p38MAPK phosphorylation in the DRG neuron leads to peripherally-driven hyperalgesia during the early post-infusion period, while spinal dynorphin-bradykinin signaling promotes hyperalgesia during the late post-infusion period.

进行本研究以确定负责瑞芬太尼诱导的痛觉过敏的神经元基因座和个体分子机制。评估了甲基纳曲酮（MNX）对瑞芬太尼诱导的行为痛觉过敏的作用，以区分外周和/或中枢神经系统对瑞芬太尼诱导的痛觉过敏的作用。研究了瑞芬太尼输注后背根神经节（DRG）神经元中p38丝裂原活化蛋白激酶（p38MAPK）的磷酸化，以及p38MAPK抑制剂对瑞芬太尼引起的痛觉过敏的影响，以研究p38MAPK参与瑞芬太尼的外周机制诱发痛觉过敏。瑞芬太尼输注后脊柱前强啡肽mRNA水平，并研究了BK2缓激肽受体拮抗剂对瑞芬太尼诱导的痛觉过敏的作用，以评估潜在的脊髓机制。还使用行为分析研究了MNX和BK2拮抗剂对瑞芬太尼诱导的切口后痛觉过敏加重的影响。瑞芬太尼输注在输注后的早期（4 h至2天）和晚期（8-14天）引起痛觉过敏。MNX仅在输液后早期抑制痛觉过敏。在输注后早期，在DRG神经元中观察到了p38MAPK磷酸化，并且p38MAPK抑制剂抑制了痛觉过敏。输注后晚期，前强啡肽在脊髓中的表达增加，并且BK2拮抗剂抑制痛觉过敏。MNX和BK2拮抗剂抑制瑞芬太尼诱导的切口痛觉过敏加重。本研究表明瑞芬太尼激活外周和脊髓神经元，以促进按时间顺序排列的痛觉过​​敏。DRG神经元中的p38MAPK磷酸化在输注后早期会导致周围性痛觉过敏，而脊髓强啡肽-缓激肽信号传导会在输注后晚期促进痛觉过敏。