Department of Anesthesiology, University of Kentucky, Lexington, KY 40536-0293, USA.
Eur J Pharmacol. 2011 Jan 25;651(1-3):89-95. doi: 10.1016/j.ejphar.2010.10.083. Epub 2010 Nov 30.
In addition to analgesia opioids may also enhance pain sensitivity. Opioid-induced hyperalgesia, typically associated with potent mu-opioid agonists (e.g. fentanyl, morphine, and heroin), may be of clinical importance due to the possible counteraction of analgesia and/or paradoxical enhancement of a pre-existing pain condition during opioid therapy. Buprenorphine, a potent opioid analgesic, has a complex pharmacology on mu and kappa receptors. Buprenorphine has a better analgesia/toxicity profile (a ceiling effect for respiratory depression, less potential for abuse) compared to typical mu-opioids. Little is known about buprenorphine-induced hyperalgesia. Potentially, a lack of hyperalgesia with these other characteristics could make buprenorphine a more desirable opioid for management of chronic pain. Responsiveness to high and ultra-low doses of buprenorphine was examined following acute and repeated administration in a rat model of thermal nociception (the tail-flick test). Buprenorphine produced a dose-related antinociception. Loss of efficacy (tolerance) followed by enhanced pain sensitivity occurred with repeated dosing of buprenorphine. Delayed hyperalgesia, seen in association with antinociceptive tolerance, was blocked by the NMDA receptor antagonist, ketamine. Buprenorphine (ultra-low dose) resulted in immediate hyperalgesia, which was also reversed by ketamine, in a dose-related fashion. No tolerance to hyperalgesia was seen with repeated dosing of low-dose buprenorphine. The antinociceptive effect of buprenorphine was diminished in rats, which previously exhibited hyperalgesia with buprenorphine. In summary, bimodal properties of buprenoprhine were separately demonstrated: pronociceptive at ultra-low dose and antinociceptive at higher doses. An NMDA-receptor mechanism was involved in hyperalgesia with buprenorphine.
除了镇痛作用，阿片类药物还可能增强疼痛敏感性。阿片类药物引起的痛觉过敏，通常与强效 μ 阿片受体激动剂（如芬太尼、吗啡和海洛因）相关，可能具有重要的临床意义，因为在阿片类药物治疗期间，可能会出现镇痛作用的拮抗作用和/或对先前存在的疼痛状况的反常增强。丁丙诺啡是一种强效阿片类镇痛药，对 μ 和 κ 受体具有复杂的药理学作用。与典型的 μ 阿片类药物相比，丁丙诺啡具有更好的镇痛/毒性特征（呼吸抑制的天花板效应，滥用潜力较小）。关于丁丙诺啡引起的痛觉过敏知之甚少。这些其他特性缺乏痛觉过敏可能使丁丙诺啡成为治疗慢性疼痛更理想的阿片类药物。在热伤害感受性（尾巴闪烁测试）的大鼠模型中，在急性和重复给药后，研究了对丁丙诺啡高剂量和超低剂量的反应性。丁丙诺啡呈剂量相关的镇痛作用。随着丁丙诺啡的重复给药，出现了疗效丧失（耐受），随后出现了疼痛敏感性增强。与镇痛耐受相关的延迟性痛觉过敏被 NMDA 受体拮抗剂氯胺酮阻断。丁丙诺啡（超低剂量）立即引起痛觉过敏，氯胺酮也以剂量相关的方式逆转，重复给予低剂量丁丙诺啡不会产生痛觉过敏耐受。在先前表现出丁丙诺啡引起的痛觉过敏的大鼠中，丁丙诺啡的镇痛作用减弱。总之，丁丙诺啡具有双模态特性：超低剂量时具有致痛作用，高剂量时具有镇痛作用。NMDA 受体机制参与了丁丙诺啡的痛觉过敏。
