Kumar Priyank, Sunkaraneni Soujanya, 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.
Eur J Pharmacol. 2008 Nov 12;597(1-3):39-45. doi: 10.1016/j.ejphar.2008.08.025. Epub 2008 Aug 30.
This study examined the antinociceptive (analgesic) efficacy of hydromorphone and hydromorphone-induced tolerance and regulation of mu-opioid receptor density. Initially s.c. hydromorphone's time of peak analgesic (tail-flick) effect (45 min) and ED50 using standard and cumulative dosing protocols (0.22 mg/kg, 0.37 mg/kg, respectively) were determined. The apparent analgesic efficacy (tau) of hydromorphone was then estimated using the operational model of agonism and the irreversible mu-opioid receptor antagonist clocinnamox. Mice were injected with clocinnamox (0.32-25.6 mg/kg, i.p.) and 24 h later, the analgesic potency of hydromorphone was determined. The tau value for hydromorphone was 35, which suggested that hydromorphone is a lower analgesic efficacy opioid agonist. To examine hydromorphone-induced tolerance, mice were continuously infused s.c. with hydromorphone (2.1-31.5 mg/kg/day) for 7 days and then morphine cumulative dose response studies were performed. Other groups of mice were injected with hydromorphone (2.2-22 mg/kg/day) once, or intermittently every 24 h for 7 days. Twenty-four hours after the last injection, mice were tested using morphine cumulative dosing studies. There was more tolerance with infusion treatments compared to intermittent treatment. When compared to higher analgesic efficacy opioids, hydromorphone infusions induced substantially more tolerance. Finally, the effect of chronic infusion (31.5 mg/kg/day) and 7 day intermittent (22 mg/kg/day) hydromorphone treatment on spinal cord mu-opioid receptor density was determined. Hydromorphone did not produce any change in mu-opioid receptor density following either treatment. These results support suggestions that analgesic efficacy is correlated with tolerance magnitude and regulation of mu-opioid receptors when opioid agonists are continuously administered. Taken together, these studies indicate that analgesic efficacy and treatment protocol are important in determining tolerance and regulation of mu-opioid receptors.
本研究考察了氢吗啡酮的抗伤害感受（镇痛）效能、氢吗啡酮诱导的耐受性以及μ-阿片受体密度的调节。最初，通过标准给药方案和累积给药方案（分别为0.22mg/kg、0.37mg/kg）确定了皮下注射氢吗啡酮的镇痛（甩尾）效应峰值时间（45分钟）和半数有效剂量（ED50）。然后，使用激动作用操作模型和不可逆的μ-阿片受体拮抗剂氯辛那明来估计氢吗啡酮的表观镇痛效能（τ）。给小鼠腹腔注射氯辛那明（0.32 - 25.6mg/kg），24小时后，测定氢吗啡酮的镇痛效力。氢吗啡酮的τ值为35，这表明氢吗啡酮是一种镇痛效能较低的阿片类激动剂。为了考察氢吗啡酮诱导的耐受性，给小鼠连续7天皮下输注氢吗啡酮（2.1 - 31.5mg/kg/天），然后进行吗啡累积剂量反应研究。其他组小鼠分别单次注射氢吗啡酮（2.2 - 22mg/kg/天），或每24小时间歇注射7天。最后一次注射24小时后，使用吗啡累积给药研究对小鼠进行测试。与间歇治疗相比，输注治疗产生的耐受性更强。与镇痛效能较高的阿片类药物相比，氢吗啡酮输注诱导的耐受性明显更强。最后，确定了慢性输注（31.5mg/kg/天）和7天间歇性（22mg/kg/天）氢吗啡酮治疗对脊髓μ-阿片受体密度的影响。两种治疗后，氢吗啡酮均未引起μ-阿片受体密度的任何变化。这些结果支持了以下观点：当持续给予阿片类激动剂时，镇痛效能与耐受性程度以及μ-阿片受体的调节相关。综上所述，这些研究表明镇痛效能和治疗方案在确定μ-阿片受体的耐受性和调节方面很重要。
