Holtman Joseph R, Wala Elzbieta P
University of Kentucky, Chandler Medical Center, Department of Anesthesiology, Lexington Kentucky 40536-0293, USA.
Anesthesiology. 2007 Mar;106(3):563-71. doi: 10.1097/00000542-200703000-00022.
Recently, it has been appreciated that in addition to their antinociceptive properties, opioid analgesics also can enhance pain sensitivity (opioid-induced hyperalgesia [OIH]). OIH may enhance preexisting pain and contribute to dose escalation, tolerance, and misuse/abuse of opioids. Better information is needed to determine which opioid or opioid combinations may be least likely to produce OIH and therefore possibly represent better choices for pain management. Herein the authors have examined the hyperalgesic and antinociceptive properties of racemic methadone and its enantiomers alone and in combination with morphine in rats. Methadone is of particular interest because it possesses both micro-receptor agonist and N-methyl-d-aspartate receptor antagonist activities.
The antinociceptive and hyperalgesic properties of d,l-methadone, l-methadone, and d-methadone were characterized by dose and sex using the thermal tail-flick test (high and low intensity). The responses to l- and d-methadone combinations with morphine were also determined with this model.
Antinociceptive and hyperalgesic effects of d,l-methadone were demonstrated. These effects were related to dose but not to sex. The degree of hyperalgesia was greater with l-methadone compared with d,l-methadone. In contrast, d-methadone (N-methyl-d-aspartate antagonist) did not produce hyperalgesia. Furthermore, d-methadone blocked morphine hyperalgesia, enhanced antinociception, and abolished sex-related differences. This seems to be the result of antagonistic activity of d-methadone at the N-methyl-d-aspartate receptor.
The current findings with methadone are supportive of previous findings implicating mu-opioid and N-methyl-d-aspartate receptor mechanisms in OIH. Better understanding of OIH may help in choosing the most appropriate opioids for use in the treatment of pain.
最近人们认识到，阿片类镇痛药除了具有镇痛特性外，还可增强疼痛敏感性（阿片类药物诱导的痛觉过敏[OIH]）。OIH可能会加重已有的疼痛，并导致剂量增加、耐受性以及阿片类药物的滥用/误用。需要更完善的信息来确定哪种阿片类药物或阿片类药物组合产生OIH的可能性最小，因此可能是疼痛管理的更佳选择。在此，作者研究了消旋美沙酮及其对映体单独使用以及与吗啡联合使用时在大鼠中的痛觉过敏和镇痛特性。美沙酮特别引人关注，因为它兼具微受体激动剂和N-甲基-D-天冬氨酸受体拮抗剂活性。
使用热甩尾试验（高强度和低强度），按剂量和性别对消旋美沙酮、左旋美沙酮和右旋美沙酮的镇痛和痛觉过敏特性进行了表征。该模型还确定了左旋和右旋美沙酮与吗啡联合使用时的反应。
证实了消旋美沙酮的镇痛和痛觉过敏作用。这些作用与剂量有关，而与性别无关。与消旋美沙酮相比，左旋美沙酮的痛觉过敏程度更高。相比之下，右旋美沙酮（N-甲基-D-天冬氨酸拮抗剂）未产生痛觉过敏。此外，右旋美沙酮可阻断吗啡引起的痛觉过敏，增强镇痛作用，并消除性别相关差异。这似乎是右旋美沙酮在N-甲基-D-天冬氨酸受体上的拮抗活性所致。
目前关于美沙酮的研究结果支持了先前有关μ-阿片受体和N-甲基-D-天冬氨酸受体机制参与OIH的研究结果。对OIH的更好理解可能有助于选择最适合用于疼痛治疗的阿片类药物。
