Kangas Brian D, Bergman Jack
Harvard Medical School, McLean Hospital, Belmont, MA, USA.
Pain. 2014 Sep;155(9):1821-1828. doi: 10.1016/j.pain.2014.06.010. Epub 2014 Jun 23.
The effective management of pain is a longstanding public health concern. Morphine-like opioids have long been front-line analgesics, but produce undesirable side effects that can limit their application. Slow progress in the introduction of novel improved medications for pain management over the last 5 decades has prompted a call for innovative translational research, including new preclinical assays. Most current in vivo procedures (eg, tail flick, hot plate, warm water tail withdrawal) assay the effects of nociceptive stimuli on simple spinal reflexes or unconditioned behavioral reactions. However, clinical treatment goals may include the restoration of previous behavioral activities, which can be limited by medication-related side effects that are not measured in such procedures. The present studies describe an apparatus and procedure to study the disruptive effects of nociceptive stimuli on voluntary behavior in nonhuman primates, and the ability of drugs to restore such behavior through their analgesic actions. Squirrel monkeys were trained to pull a cylindrical thermode for access to a highly palatable food. Next, sessions were conducted in which the temperature of the thermode was increased stepwise until responding stopped, permitting the determination of stable nociceptive thresholds. Tests revealed that several opioid analgesics, but not d-amphetamine or Δ(9)-THC, produced dose-related increases in threshold that were antagonist sensitive and efficacy dependent, consistent with their effects using traditional measures of antinociception. Unlike traditional reflex-based measures, however, the results also permitted the concurrent evaluation of response disruption, providing an index with which to characterize the behavioral selectivity of antinociceptive drugs.
疼痛的有效管理是一个长期存在的公共卫生问题。吗啡类阿片长期以来一直是一线镇痛药，但会产生不良副作用，从而限制其应用。在过去50年里，用于疼痛管理的新型改良药物引入进展缓慢，这促使人们呼吁开展创新性转化研究，包括新的临床前试验。目前大多数体内试验程序（如甩尾试验、热板试验、温水甩尾试验）检测伤害性刺激对简单脊髓反射或非条件行为反应的影响。然而，临床治疗目标可能包括恢复先前的行为活动，而这可能会受到此类试验程序未测量的药物相关副作用的限制。本研究描述了一种装置和程序，用于研究伤害性刺激对非人灵长类动物自愿行为的干扰作用，以及药物通过其镇痛作用恢复此类行为的能力。松鼠猴经过训练，拉动圆柱形热刺激器以获取美味食物。接下来，进行试验，逐步提高热刺激器的温度，直到反应停止，从而确定稳定的伤害性阈值。测试表明，几种阿片类镇痛药，但不是右旋苯丙胺或Δ(9)-四氢大麻酚，产生了与剂量相关的阈值升高，这种升高对拮抗剂敏感且依赖于药效，这与它们使用传统抗伤害感受测量方法的效果一致。然而，与传统的基于反射的测量方法不同，这些结果还允许同时评估反应干扰情况，提供一个指标来表征抗伤害感受药物的行为选择性。
