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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Chronic l-alpha-acetylmethadol (LAAM) in rhesus monkeys: tolerance and cross-tolerance to the antinociceptive, ventilatory, and rate-decreasing effects of opioids.
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Chronic l-alpha-acetylmethadol (LAAM) in rhesus monkeys: tolerance and cross-tolerance to the antinociceptive, ventilatory, and rate-decreasing effects of opioids.

机译：恒河猴中的慢性l-α-乙酰甲基美沙多（LAAM）：对阿片类药物的抗伤害感受性，通气性和降速作用的耐受性和交叉耐受性。

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Although l-alpha-acetylmethadol (LAAM) is a maintenance treatment for opioid dependence, few studies have systematically assessed the behavioral effects of LAAM and other drugs in LAAM-treated subjects. In the current study, we assessed the ventilatory, antinociceptive, and rate-decreasing effects of drugs (s.c. except dynorphin, which was administered i.v.) in rhesus monkeys (n = 3 or 4) before and during chronic treatment with 1.0 mg/kg/12 h LAAM (s.c.). Minute volume (V(E)) was reduced to 62% of baseline during LAAM treatment and remained depressed after more than 10 months of LAAM treatment. A cumulative dose of 10.0 mg/kg morphine decreased V(E) to similar values under baseline (53%) and LAAM-treated (52%) conditions; however, larger doses of morphine (up to 56.0 mg/kg) could be administered safely to LAAM-treated monkeys. LAAM treatment produced dependence as evidenced by a 220% increase in V(E) after a dose of naltrexone (0.032 mg/kg) that did not modify ventilation under baseline conditions. Compared with baseline, LAAM treatment increased the ED(50) values for the rate-decreasing effects of nalbuphine, morphine, and alfentanil by 7-, 7-, and 2-fold, respectively, in monkeys responding under a fixed ratio 10 schedule of food presentation. Similarly, LAAM treatment increased ED(50) values for the antinociceptive effects of morphine and alfentanil by 5- and 3-fold, respectively. LAAM treatment also increased the ED(50) values for the antinociceptive effects of the kappa-agonist enadoline by 5-fold and not those of U-50,488. That tolerance developed differentially to the ventilatory, rate, and antinociceptive effects of mu-agonists in LAAM-treated monkeys suggests that cross-tolerance might not be a safe therapeutic approach for the treatment of some opioid abusers.
机译：尽管l-α-乙酰基甲氧灵（LAAM）是维持阿片类药物依赖性的治疗方法，但很少有研究系统地评估了LAAM和其他药物对LAAM治疗的受试者的行为影响。在本研究中，我们评估了在用1.0 mg / kg / kg的慢性治疗前后，恒河猴（n = 3或4）中药物（sc的强啡肽除外）的通气，抗伤害性和降速作用。 LAAM（sc）12小时。在LAAM治疗期间，每分钟体积（V（E））降至基线的62％，并且在LAAM治疗超过10个月后仍然保持低迷状态。在基线（53％）和经LAAM处理（52％）的条件下，累积剂量10.0 mg / kg吗啡使V（E）降低至相似值;但是，可以安全地将更大剂量的吗啡（最高56.0 mg / kg）施用于经LAAM治疗的猴子。 LAAM治疗产生依赖性，如在基线条件下服用纳曲酮（0.032 mg / kg）后不改变通气量，则V（E）增加220％即可证明。与基线相比，LAAM处理在固定比例10日程下对纳布啡，吗啡和阿芬太尼降速作用的ED（50）值分别增加了7倍，7倍和2倍。食物介绍。类似地，LAAM处理使吗啡和阿芬太尼的抗伤害感受作用的ED（50）值分别提高了5倍和3倍。 LAAM处理还可以将κ-激动剂依诺林的镇痛效果的ED（50）值提高5倍，而不是U-50488的ED（50）值。这种耐受性与mu-激动剂在LAAM治疗的猴子中的通气，速率和抗伤害感受作用不同，这表明交叉耐受可能不是治疗某些阿片类药物滥用者的安全治疗方法。

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