Comparative and Molecular Biosciences, University of Minnesota College of Veterinary Medicine, St Paul, MN, United States of America.
Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, United States of America.
PLoS One. 2024 Mar 21;19(3):e0298819. doi: 10.1371/journal.pone.0298819. eCollection 2024.
Buprenorphine in an extended-release formulation intended for use in laboratory subjects is frequently administered to rats to provide extended analgesia without repeated handling. While levels of buprenorphine may persist in serum once extended-release buprenorphine has been introduced, exposure to opioids can cause opioid tolerance or opioid-induced hypersensitivity. This work examined the analgesic duration and efficacy of a single administration of extended-release buprenorphine intended for use in laboratory subjects in models of inflammatory pain and post-operative pain and the development of opioid tolerance in rat. After subcutaneous administration of 1 mg/kg extended-release buprenorphine, analgesic efficacy did not persist for the expected 72 hours. No changes were observed in mechanical thresholds in the hindpaws that were contralateral to the injury, suggesting a lack of centrally mediated opioid-induced hypersensitivity. To determine whether opioid tolerance arose acutely after one exposure to extended-release buprenorphine, we conducted the warm water tail flick assay; on Day 1 we administered either saline or extended-release buprenorphine (1 mg/kg) and on Day 3 we quantified the standard buprenorphine dose-response curve (0.1-3 mg/kg). Rats previously given extended-release buprenorphine displayed decreased analgesic responses after administration of standard buprenorphine as compared to the robust efficacy of standard buprenorphine in control subjects. Males appeared to show evidence of acute opioid tolerance, while females previously exposed to opioid did not demonstrate a decreased response at the doses examined. Taken together, these results suggest that opioid tolerance arises quickly in male rats after exposure to the extended-release formulation of buprenorphine. This tolerance may account for the brief period of antinociception observed.
美沙酮控释制剂常用于实验室动物，常被用于给大鼠投药以提供长效镇痛而无需反复处理。虽然美沙酮控释制剂投药后血清中药物水平可能持续存在，但接触阿片类药物会导致阿片类药物耐受或阿片类药物诱导的超敏反应。本研究旨在检查单次给予实验室用美沙酮控释制剂在炎症性疼痛和术后疼痛模型中的镇痛持续时间和疗效，以及该制剂在大鼠中的阿片类药物耐受发展情况。在给予 1mg/kg 美沙酮控释制剂皮下给药后，预计 72 小时内的镇痛效果并未持续。受伤对侧后肢的机械阈值没有变化，这表明缺乏中枢介导的阿片类药物诱导的超敏反应。为了确定单次接触美沙酮控释制剂后是否会急性产生阿片类药物耐受，我们进行了热尾 flick 试验；在第 1 天，我们给予生理盐水或美沙酮控释制剂（1mg/kg），在第 3 天，我们量化了标准美沙酮剂量反应曲线（0.1-3mg/kg）。与对照组中标准美沙酮的强大疗效相比，先前给予美沙酮控释制剂的大鼠在给予标准美沙酮后显示出镇痛反应降低。雄性大鼠似乎出现了急性阿片类药物耐受的证据，而先前接触过阿片类药物的雌性大鼠在检查的剂量下并未表现出反应降低。总之，这些结果表明，雄性大鼠在接触美沙酮控释制剂后很快产生阿片类药物耐受。这种耐受可能解释了观察到的短暂镇痛作用。
