Effects of Cannabinoids on Pain-Stimulated and Pain-Depressed Behavior in Rats

描述（由申请人提供）：疼痛是医用大麻的主要适应症之一，新型大麻素（CB）药物正在开发中，可作为候选镇痛药。然而，CBs作为镇痛药的经验支持一直不一致。大麻的主要活性成分9-四氢大麻酚（THC）和其他CB的抗伤害性功效已在许多急性和慢性炎性疼痛的临床前试验中得到证实。相比之下，CB在人类中的镇痛作用是不可靠的。临床前和临床结果之间的这种差异可能与临床前研究过度依赖于测量疼痛刺激行为（定义为在递送有害刺激后速率和/或强度增加的行为）的测定有关。这些测定中的抗伤害感受由疼痛刺激行为的减少指示，其可以由对有害刺激的感觉敏感性的降低（即真正的镇痛）或假阳性运动损伤产生。本申请提出疼痛刺激行为的临床前测定易受与CB诱导的运动损伤相关的假阳性效应的影响，从而高估CB镇痛功效。我们建议通过评估CB在疼痛抑制行为的新测定中的作用来解决这一弱点。疼痛抑制行为的测定评估在递送有害刺激后速率和/或强度降低的行为，并且这些测定中的抗伤害感受由行为的增加指示。该特征使得疼痛抑制行为的测定对假阳性运动损伤不敏感。此外，疼痛抑郁行为的测定模型临床相关的疼痛相关的功能障碍和抑郁情绪。在一个示例中，在递送电刺激之后，抑制用于颅内自刺激（ICSS）的杠杆按压。 腹腔内注射乳酸，这种疼痛诱导的ICSS抑制被经典的镇痛药阻断。重要的是，ICSS的疼痛诱导的抑郁不被κ阿片激动剂和多巴胺拮抗剂阻断，这些药物在疼痛刺激行为的测定中产生假阳性抗伤害感受，但对治疗人类疼痛无效。因为没有研究评估CB在疼痛抑制行为测定中的作用，所以本申请提出评估多种CB受体选择性和非选择性化合物在疼痛刺激和疼痛抑制行为的互补测定中的作用。[我假设在急性炎性疼痛条件下CB诱导的抗伤害感受是由假阳性运动损伤介导的。相反，在慢性炎症期间，CB受体在免疫系统中上调，我假设CB会产生真正的抗伤害感受。该项目的主要目标是使用可能更能预测人类镇痛的模型来评估CB的抗伤害感受作用。

DESCRIPTION (provided by applicant): Pain is one of the primary indications for medical marijuana and novel cannabinoid (CB) drugs are under development as candidate analgesics. However, empirical support for CBs as analgesics has been inconsistent. The antinociceptive efficacy of ¿9-tetrahydrocannabinol (THC), the primary active constituent of marijuana, and other CBs has been demonstrated in many preclinical assays of acute and chronic inflammatory pain. Contrastingly, the analgesic effects of CBs in humans have been unreliable. This discrepancy between preclinical and clinical results may be associated with an overreliance of preclinical research on assays that measure PAIN-STIMULATED BEHAVIOR, defined as behavior that is increased in rate and/or intensity following delivery of a noxious stimulus. Antinociception in these assays is indicated by a decrease in pain-stimulated behaviors, which can be produced by either a decrease in sensory sensitivity to a noxious stimulus (i.e. true analgesia) or by false positive motor impairment. This application proposes that preclinical assays of pain-stimulated behavior are vulnerable to false-positive effects associated with CB- induced motor impairment and thereby overestimate CB analgesic efficacy. We propose to address this weakness by assessing the effects of CBs in a novel assay of PAIN-DEPRESSED BEHAVIOR. Assays of pain-depressed behavior assess behavior that is decreased in rate and/or intensity following delivery of a noxious stimulus, and antinociception in these assays is indicated by increases in behavior. This feature renders assays of pain-depressed behavior insensitive to false positive motor impairment. Additionally, assays of pain-depressed behavior model clinically relevant pain-related functional impairment and depressed mood. In one example, lever pressing for intracranial self-stimulation (ICSS) is depressed following delivery of an intraperitoneal injection of lactic acid and this pain-induced depression of ICSS is blocked by classic analgesics. Importantly, pain-induced depression of ICSS is not blocked by kappa opioid agonists and dopamine antagonists, drugs that produce false positive antinociception in assays of pain-stimulated behavior but are ineffective to treat pain in humans. Because no studies have evaluated the effects of CBs in assays of pain- depressed behavior, this application proposes to assess the effects of a variety of CB receptor-selective and -nonselective compounds in complementary assays of pain-stimulated and pain-depressed behavior. [I hypothesize that CB-induced antinociception under conditions of acute inflammatory pain is mediated by false- positive motor-impairment. Contrastingly, during chronic inflammation in which CB receptors are upregulated in the immune system, I hypothesize that CBs will produce true antinociception.] The primary goal of this project is to assess antinociceptive effects of CBs using a model that may be more predictive of analgesia in humans.