Célèrier E, Rivat C, Jun Y, Laulin J P, Larcher A, Reynier P, Simonnet G
Institut National de la Santé et de la Recherche Médicale (INSERM) U 259, Bordeaux, France.
Anesthesiology. 2000 Feb;92(2):465-72. doi: 10.1097/00000542-200002000-00029.
It has been reported that mu-opioid receptor activation leads to a sustained increase in glutamate synaptic effectiveness at the N-methyl-D-aspartate (NMDA) receptor level, a system associated with central hypersensitivity to pain. One hypothesis is that postoperative pain may result partly from the activation of NMDA pain facilitatory processes induced by opiate treatment per se. The authors tested here the effectiveness of the opiate analgesic fentanyl for eliciting a delayed enhancement in pain sensitivity.
The consequences of four bolus injections (every 15 min) of fentanyl (20-100 microg/kg per injection, subcutaneously) on immediate (for several hours) and long-term (for several days) sensitivity to nociceptive stimuli in the rat (paw-pressure vocalization test) were evaluated. The effects of the combination of the NMDA-receptor antagonist ketamine (10 mg/kg, subcutaneously) with fentanyl also were assessed.
Fentanyl administration exhibited a biphasic time-dependent effect: first, an early response (for 2-5 h) associated with a marked increase in nociceptive threshold (analgesia), and second, a later response associated with sustained lowering of the nociceptive threshold (5 days for the longest effect) below the basal value (30% of decrease for the maximal effect) indicative of hyperalgesia. The higher the fentanyl dose used, the more pronounced was the fentanyl-induced hyperalgesia. Ketamine pretreatment, which had no analgesic effect on its own, enhanced the earlier response (analgesia) and prevented the development of long-lasting hyperalgesia.
Fentanyl activates NMDA pain facilitatory processes, which oppose analgesia and lead to long-lasting enhancement in pain sensitivity.
据报道，μ-阿片受体激活会导致N-甲基-D-天冬氨酸（NMDA）受体水平的谷氨酸突触效能持续增加，该系统与中枢性疼痛超敏反应相关。一种假说认为，术后疼痛可能部分源于阿片类药物治疗本身诱导的NMDA疼痛促进过程的激活。作者在此测试了阿片类镇痛药芬太尼引发疼痛敏感性延迟增强的有效性。
评估了四次推注（每15分钟一次）芬太尼（每次皮下注射20 - 100微克/千克）对大鼠即刻（数小时）和长期（数天）对伤害性刺激的敏感性（爪部压力发声试验）的影响。还评估了NMDA受体拮抗剂氯胺酮（10毫克/千克，皮下注射）与芬太尼联合使用的效果。
芬太尼给药呈现出双相的时间依赖性效应：首先，早期反应（持续2 - 5小时）与伤害性阈值显著升高（镇痛）相关；其次，后期反应与伤害性阈值持续降低（最长效应持续5天）至基础值以下（最大效应时降低30%）相关，表明存在痛觉过敏。使用的芬太尼剂量越高，芬太尼诱导的痛觉过敏就越明显。氯胺酮预处理本身无镇痛作用，但增强了早期反应（镇痛）并防止了持久痛觉过敏的发生。
芬太尼激活NMDA疼痛促进过程，这会对抗镇痛作用并导致疼痛敏感性的持久增强。
