Sirohi Sunil, Dighe Shveta V, Walker Ellen A, Yoburn Byron C
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Pharmacol Biochem Behav. 2008 Nov;91(1):115-20. doi: 10.1016/j.pbb.2008.06.019. Epub 2008 Jun 30.
This study determined if fentanyl analgesic efficacy predicts the magnitude of tolerance and mu-opioid receptor regulation. To estimate efficacy, mice were injected i.p. with saline or clocinnamox (CCAM), an irreversible mu-opioid receptor antagonist, (0.32-25.6 mg/kg) and 24 h later fentanyl cumulative dose-response studies were conducted. CCAM dose dependently shifted the fentanyl dose-response function to the right. The apparent efficacy (tau) of fentanyl, based on the operational model of agonism, was estimated as 58, indicating that fentanyl is a high analgesic efficacy agonist. Next, mice were infused with fentanyl (1, 2 or 4 mg/kg/day) for 7 days. Controls were implanted with placebo pellets. At the end of 7 days, morphine cumulative dose-response studies or mu-opioid receptor saturation binding studies were conducted. Fentanyl infusions dose dependently decreased morphine potency with the highest fentanyl dose reducing morphine potency by approximately 6 fold. Chronic infusion with fentanyl (4 mg/kg/day) significantly reduced mu-opioid receptor density by 28% without altering affinity, whereas lower infusion doses had no effect. Taken together, the present results strengthen the proposal that opioid analgesic efficacy predicts mu-opioid receptor regulation and the magnitude of tolerance.
本研究确定了芬太尼的镇痛效果是否能预测耐受性的程度和μ-阿片受体的调节。为评估效果，给小鼠腹腔注射生理盐水或氯西诺昔（CCAM，一种不可逆的μ-阿片受体拮抗剂，剂量为0.32 - 25.6 mg/kg），24小时后进行芬太尼累积剂量反应研究。CCAM剂量依赖性地使芬太尼剂量反应函数右移。根据激动作用的操作模型，芬太尼的表观效果（τ）估计为58，表明芬太尼是一种高镇痛效果的激动剂。接下来，给小鼠输注芬太尼（1、2或4 mg/kg/天），持续7天。对照组植入安慰剂药丸。在7天结束时，进行吗啡累积剂量反应研究或μ-阿片受体饱和结合研究。芬太尼输注剂量依赖性地降低吗啡效力，最高剂量的芬太尼使吗啡效力降低约6倍。长期输注芬太尼（4 mg/kg/天）可使μ-阿片受体密度显著降低28%，而亲和力不变，而较低的输注剂量则无影响。综上所述，目前的结果支持了阿片类药物镇痛效果可预测μ-阿片受体调节和耐受性程度这一观点。
