Shen K F, Crain S M
Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
Brain Res. 1997 May 23;757(2):176-90. doi: 10.1016/s0006-8993(97)00197-2.
In previous studies we showed that low (pM) concentrations of naloxone (NLX), naltrexone (NTX) or etorphine selectively antagonize excitatory, but not inhibitory, opioid receptor-mediated functions in nociceptive types of sensory neurons in culture. Cotreatment of these neurons with pM NTX or etorphine not only results in marked enhancement of the inhibitory potency of acutely applied nM morphine [or other bimodally-acting (inhibitory/excitatory) opioid agonists], but also prevents development of cellular manifestations of tolerance and dependence during chronic exposure to microM morphine. These in vitro studies were confirmed in vivo by demonstrating that acute cotreatment of mice with morphine plus a remarkably low dose of NTX (ca. 10 ng/kg) does, in fact, enhance the antinociceptive potency of morphine, as measured by hot-water tail-flick assays. Furthermore, chronic cotreatment of mice with morphine plus low doses of NTX markedly attenuates development of naloxone-precipitated withdrawal-jumping in physical dependence assays. The present study provides systematic dose-response analyses indicating that NTX elicited optimal enhancement of morphine's antinociceptive potency in mice when co-administered (i.p.) at about 100 ng/kg together with morphine (3 mg/kg). Doses of NTX as low as 1 ng/kg or as high as 1 microg/kg were still effective, but to a lesser degree. Oral administration of NTX in the drinking water of mice was equally effective as i.p. injections in enhancing the antinociceptive potency of acute morphine injections and even more effective in attenuating development of tolerance and NLX-precipitated withdrawal-jumping during chronic cotreatment. Cotreatment with a subanalgesic dose of etorphine (10 ng/kg) was equally effective as NTX in enhancing morphine's antinociceptive potency and attenuating withdrawal-jumping after chronic exposure. These studies provide a rationale for the clinical use of ultra-low-dose NTX or etorphine so as to increase the antinociceptive potency while attenuating the tolerance/dependence liability of morphine or other conventional bimodally-acting opioid analgesics.
在先前的研究中，我们发现低浓度（皮摩尔）的纳洛酮（NLX）、纳曲酮（NTX）或埃托啡能选择性地拮抗培养的伤害性感觉神经元中兴奋性而非抑制性阿片受体介导的功能。用皮摩尔浓度的NTX或埃托啡共同处理这些神经元，不仅会显著增强急性应用纳摩尔吗啡[或其他具有双相作用（抑制性/兴奋性）的阿片类激动剂]的抑制效力，还能防止在长期暴露于微摩尔吗啡期间出现耐受性和依赖性的细胞表现。这些体外研究在体内得到了证实，通过证明用吗啡加极低剂量的NTX（约10纳克/千克）对小鼠进行急性共同处理，实际上确实增强了吗啡的镇痛效力，这是通过热水甩尾试验测量的。此外，用吗啡加低剂量的NTX对小鼠进行慢性共同处理，在身体依赖性试验中能显著减轻纳洛酮诱发的戒断跳跃反应。本研究提供了系统的剂量反应分析，表明当NTX与吗啡（3毫克/千克）腹腔注射共同给药时，以约100纳克/千克的剂量能使小鼠体内吗啡的镇痛效力得到最佳增强。低至1纳克/千克或高达1微克/千克的NTX剂量仍然有效，但程度较小。在小鼠饮用水中口服NTX与腹腔注射在增强急性吗啡注射的镇痛效力方面同样有效，并且在慢性共同处理期间减轻耐受性和纳洛酮诱发的戒断跳跃反应方面甚至更有效。用亚镇痛剂量的埃托啡（10纳克/千克）共同处理在增强吗啡的镇痛效力和减轻慢性暴露后的戒断跳跃反应方面与NTX同样有效。这些研究为超低剂量NTX或埃托啡的临床应用提供了理论依据，以便在增强镇痛效力的同时减轻吗啡或其他传统双相作用阿片类镇痛药的耐受性/依赖性。
