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

描述(申请人提供)：疼痛是医用大麻的主要适应症之一，新型大麻(CB)药物正在开发中，作为候选止痛药。然而，对CBS作为止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CBS已经在许多急性和慢性炎症性疼痛的临床前试验中证明了抗伤害效应。相比之下，CBS对人类的止痛效果并不可靠。这种临床前和临床结果之间的差异可能与临床前研究过度依赖于测量疼痛刺激行为的分析有关，疼痛刺激行为的定义是在传递有害刺激后速度和/或强度增加的行为。在这些检测中，抗伤害性感觉是指疼痛刺激行为的减少，这可能是由于对伤害性刺激(即真正的止痛)的感觉敏感度降低或假阳性运动障碍造成的。这一应用表明，疼痛刺激行为的临床前检测很容易受到与CB引起的运动损伤相关的假阳性效应的影响，因此高估了CB的止痛效果。我们建议通过评估CBS在一种新的疼痛抑郁行为分析中的效果来解决这一弱点。疼痛抑制行为的测试评估在传递有害刺激后速度和/或强度降低的行为，这些测试中的抗伤害感觉通过行为的增加来指示。这一功能使得疼痛抑郁行为的分析对假阳性运动损伤不敏感。此外，疼痛抑郁行为的分析还建立了与疼痛相关的功能障碍和抑郁情绪的临床相关模型。在一个例子中，用于颅内自我刺激(ICSS)的杠杆按压在分娩后被抑制 腹腔注射乳酸和这种疼痛引起的ICSS抑制可被经典的镇痛剂阻断。重要的是，Kappa阿片激动剂和多巴胺拮抗剂不能阻断疼痛诱导的ICSS的抑郁，这些药物在疼痛刺激行为的测试中产生假阳性的抗伤害感受，但对人类的疼痛治疗无效。由于还没有研究评估CBS在疼痛抑郁行为测试中的效果，本申请建议评估各种CB受体选择性和非选择性化合物在疼痛刺激和疼痛抑郁行为补充测试中的效果。[I假设，急性炎症性疼痛条件下CB诱导的抗伤害性感觉是由假阳性运动损伤介导的。相比之下，在慢性炎症期间，CB受体在免疫系统中上调，我假设CBS将产生真正的抗伤害感受。]该项目的主要目标是使用一种可能更能预测人类镇痛的模型来评估CBS的抗伤害效应。 与公共卫生相关：这是一个F31应用程序，用于评估传统疼痛测试中大麻类化合物的假定止痛效果，以及一种使用急性和慢性炎症性疼痛大鼠模型的疼痛相关功能损害的新测试方法。该项目的主要目标是使用一种可能更能预测人类镇痛的模型来评估大麻类药物的抗伤害性作用。

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. PUBLIC HEALTH RELEVANCE: This is a F31 application to assess the putative analgesic effects of cannabinoids in traditional assays of pain and a novel assay of pain-related functional impairment using rat models of acute and chronic inflammatory pain. The primary goal of this project is to assess the antinociceptive effects of cannabinoids using a model that may be more predictive of analgesia in humans.