Bloss J L, Hammond D L
Department of Central Nervous System Diseases Research, G.D. Searle & Co., Sokie, IL 60077.
Brain Res. 1989 Oct 16;499(2):344-56. doi: 10.1016/0006-8993(89)90783-x.
This study addressed issues concerning the validity of the shock titration paradigm by using focal, pulsed electrocutaneous stimulation and including unavoidable suprathreshold intensity stimuli among titratable, threshold intensity trials. In saline-treated monkeys, the distribution of response latencies on suprathreshold intensity trials, and the relationships between stimulus intensity and response latency, percent response or trial duration were consistent with those expected of painful stimuli. Morphine (0.3-3 mg/kg i.m.), meperidine (0.3-3 mg/kg i.m.) and pentazocine (1-6 mg/kg i.m.) each dose-dependently increased escape thresholds, but did not increase response latency on titratable trials. In contrast, diazepam (0.12-0.5 mg/kg i.m.) produced a dose-dependent increase in escape threshold and a significant increase in response latency on titratable trials. Sedative anxiolytics with muscle relaxant properties could therefore be distinguished from opioid analgesics. Morphine, meperidine, pentazocine and diazepam also produced a dose-dependent rightward shift in the frequency distribution of responses to suprathreshold stimuli at doses below those that significantly increased escape threshold. Thus, the antinociceptive effect of an opioid analgesic was detectable in the monkey in the clinically effective dose range. This paradigm permits analysis of drug effects at both escape threshold and suprathreshold intensities of noxious stimuli. The concomitant measurement of escape threshold and response latency on titratable trials with analysis of the frequency distribution of responses on suprathreshold trials yields a sensitive and discriminating analgesiometric procedure with potential application to rodent, as well as primate, species.
本研究通过使用局部脉冲电皮肤刺激，并在可滴定的阈强度试验中纳入不可避免的阈上强度刺激，探讨了休克滴定范式的有效性问题。在生理盐水处理的猴子中，阈上强度试验的反应潜伏期分布，以及刺激强度与反应潜伏期、反应百分比或试验持续时间之间的关系，与疼痛刺激所预期的一致。吗啡（0.3 - 3毫克/千克，肌肉注射）、哌替啶（0.3 - 3毫克/千克，肌肉注射）和喷他佐辛（1 - 6毫克/千克，肌肉注射）均剂量依赖性地提高了逃避阈值，但在可滴定试验中并未增加反应潜伏期。相比之下，地西泮（0.12 - 0.5毫克/千克，肌肉注射）使逃避阈值呈剂量依赖性增加，并在可滴定试验中使反应潜伏期显著增加。因此，具有肌肉松弛特性的镇静抗焦虑药可与阿片类镇痛药区分开来。吗啡、哌替啶、喷他佐辛和地西泮在低于显著提高逃避阈值的剂量下，也使对阈上刺激的反应频率分布呈剂量依赖性向右移动。因此，在临床有效剂量范围内，可在猴子中检测到阿片类镇痛药的抗伤害感受作用。该范式允许分析药物在有害刺激的逃避阈值和阈上强度时的作用。在可滴定试验中同时测量逃避阈值和反应潜伏期，并分析阈上试验的反应频率分布，可产生一种灵敏且有鉴别力的镇痛测量程序，有可能应用于啮齿动物以及灵长类动物。
