Waxman Amanda R, Arout Caroline, Caldwell Megan, Dahan Albert, Kest Benjamin
Neuropsychology Program, Queens College, City University of New York, Flushing, NY 11367, USA.
Neurosci Lett. 2009 Oct 2;462(1):68-72. doi: 10.1016/j.neulet.2009.06.061. Epub 2009 Jun 24.
Although mu-receptor opioids are clinically important analgesics, they can also paradoxically cause hyperalgesia independently of opioid receptor activity, presumably via the action of neuroexcitatory glucoronide metabolites. However, it is unknown whether the commonly used mu-receptor opioid analgesic fentanyl, which is not subject to glucuronidation, can also induce hyperalgesia independently of opioid receptor activity. Thus, here we examined whether fentanyl increases nociception on the tail-withdrawal test in CD-1 mice concurrently treated with the opioid receptor antagonist naltrexone or in opioid receptor triple knock-out mice lacking mu, delta, and kappa opioid receptors. For both groups, an acute fentanyl bolus dose (0.25mg/kg, s.c.) and continuous fentanyl infusion (cumulative daily dose: 10mg/kg) did not cause analgesia at any time. Instead, fentanyl significantly decreased withdrawal latencies relative to pre-drug values for the next 15-60 min and for six days, respectively. MK-801 blocked and reversed hyperalgesia caused by the acute injection and continuous infusion of fentanyl, respectively, in naltrexone-treated CD-1 mice, indicating the contribution of NMDA receptors to fentanyl hyperalgesia. These data show that the synthetic opioid fentanyl causes hyperalgesia independently of prior or concurrent opioid receptor activity or analgesia. Since the biotransformation of fentanyl does not yield any known pronociceptive metabolites, these data challenge assumptions regarding the role of neuroexcitatory metabolites in opioid-induced hyperalgesia.
尽管μ受体阿片类药物是临床上重要的镇痛药，但它们也可能反常地独立于阿片受体活性而导致痛觉过敏，推测是通过神经兴奋性葡萄糖醛酸代谢物的作用。然而，常用的μ受体阿片类镇痛药芬太尼不会发生葡萄糖醛酸化，它是否也能独立于阿片受体活性诱导痛觉过敏尚不清楚。因此，我们在此研究了芬太尼是否会使同时接受阿片受体拮抗剂纳曲酮治疗的CD-1小鼠或缺乏μ、δ和κ阿片受体的阿片受体三联敲除小鼠在甩尾试验中的伤害感受增加。对于这两组小鼠，急性推注芬太尼剂量（0.25mg/kg，皮下注射）和持续输注芬太尼（每日累积剂量：10mg/kg）在任何时候都未引起镇痛作用。相反，芬太尼分别在接下来的15 - 60分钟和六天内相对于给药前值显著缩短了甩尾潜伏期。MK-801分别阻断并逆转了纳曲酮治疗的CD-1小鼠中由急性注射和持续输注芬太尼引起的痛觉过敏，表明NMDA受体对芬太尼诱导的痛觉过敏有作用。这些数据表明，合成阿片类药物芬太尼独立于先前或同时存在的阿片受体活性或镇痛作用而引起痛觉过敏。由于芬太尼的生物转化不会产生任何已知的促痛代谢物，这些数据对关于神经兴奋性代谢物在阿片类药物诱导的痛觉过敏中作用的假设提出了挑战。
