Departments of Pharmacology (T.H., S.M.F., A.K.G., A.E.M., E.N.M., C.P.F.) and Psychiatry (C.P.F.) and Addiction Research, Treatment & Training Center of Excellence (T.H., S.M.F., A.K.G., A.E.M., E.N.M., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas
Departments of Pharmacology (T.H., S.M.F., A.K.G., A.E.M., E.N.M., C.P.F.) and Psychiatry (C.P.F.) and Addiction Research, Treatment & Training Center of Excellence (T.H., S.M.F., A.K.G., A.E.M., E.N.M., C.P.F.), University of Texas Health Science Center at San Antonio, San Antonio, Texas.
J Pharmacol Exp Ther. 2024 Oct 18;391(2):317-334. doi: 10.1124/jpet.124.002323.
Despite a significant decrease in the number of prescriptions for opioids, the opioid crisis continues, fueled in large part by the availability of the phenylpiperidine opioid receptor (MOR) agonist fentanyl. In contrast, the number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically, with gabapentinoids commonly detected in opioid overdose victims. Although gabapentinoids can decrease the potency of the opioid receptor antagonist naloxone to reverse heroin-induced hypoventilation in male rats, the specificity and nature of interaction between gabapentinoids and MOR agonists and any potential sex difference in those interactions are not well characterized. Gabapentinoids were studied in female and male rats discriminating fentanyl (0.0032 mg/kg, i.p.) or cocaine (3.2 mg/kg, i.p.). Alone, neither gabapentin nor pregabalin significantly increased fentanyl- or cocaine-appropriate responding. In rats discriminating fentanyl, each gabapentinoid dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the left, whereas naloxone dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the right. Each gabapentinoid (100 mg/kg) significantly decreased the potency of naloxone to antagonize the discriminative stimulus effect of fentanyl or heroin. In contrast, each gabapentinoid dose-dependently shifted the cocaine and -methamphetamine discrimination dose-effect functions to the right. There were no significant sex differences in this study. These results suggest that gabapentinoids impact the misuse of opioids, the co-use of opioids and stimulant drugs, and the increasing number of overdose deaths in individuals using opioids, stimulant drugs, and gabapentinoids in mixtures. SIGNIFICANCE STATEMENT: The number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically, with gabapentinoids commonly detected in opioid overdose victims. This study reports that in rats gabapentinoids increase the potency of fentanyl and heroin to produce discriminative stimulus effects while decreasing the potency of naloxone to antagonize those effects of fentanyl and heroin. These results can help guide policies for regulating gabapentinoids and treating opioid misuse and overdose.
尽管阿片类药物的处方数量显著减少，但阿片类药物危机仍在继续，这在很大程度上是由于苯哌啶类阿片受体（MOR）激动剂芬太尼的存在。相比之下，加巴喷丁类药物（加巴喷丁和普瑞巴林）的处方数量和非适应证使用量急剧增加，阿片类药物过量受害者中经常检测到加巴喷丁类药物。尽管加巴喷丁类药物可以降低纳洛酮（阿片受体拮抗剂）逆转雄性大鼠海洛因引起的通气不足的效力，但加巴喷丁类药物与 MOR 激动剂之间的相互作用的特异性和性质，以及这些相互作用中可能存在的性别差异，尚未得到很好的描述。研究人员在雌性和雄性大鼠中研究了芬太尼（0.0032 mg/kg，ip）或可卡因（3.2 mg/kg，ip）的辨别能力。单独使用时，加巴喷丁和普瑞巴林均未显著增加芬太尼或可卡因的适当反应。在辨别芬太尼的大鼠中，每个加巴喷丁类药物剂量依赖性地将芬太尼和海洛因的辨别剂量-效应函数向左移动，而纳洛酮剂量依赖性地将芬太尼和海洛因的辨别剂量-效应函数向右移动。每个加巴喷丁类药物（100 mg/kg）显著降低了纳洛酮拮抗芬太尼或海洛因辨别性刺激效应的效力。相比之下，每个加巴喷丁类药物剂量依赖性地将可卡因和苯丙胺的辨别剂量-效应函数向右移动。在这项研究中，没有观察到显著的性别差异。这些结果表明，加巴喷丁类药物会影响阿片类药物的滥用、阿片类药物和兴奋剂药物的共同使用，以及在同时使用阿片类药物、兴奋剂药物和加巴喷丁类药物的个体中，过量死亡人数的增加。重要声明：加巴喷丁类药物（加巴喷丁和普瑞巴林）的处方数量和非适应证使用量急剧增加，阿片类药物过量受害者中经常检测到加巴喷丁类药物。本研究报告称，在大鼠中，加巴喷丁类药物增加了芬太尼和海洛因产生辨别性刺激效应的效力，同时降低了纳洛酮拮抗这些芬太尼和海洛因效应的效力。这些结果可以帮助指导加巴喷丁类药物的监管政策以及阿片类药物滥用和过量的治疗。
