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）药物正在开发中作为候选镇痛药。然而，对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CBs的抗伤害性功效已在许多急性和慢性炎症性疼痛的临床前试验中得到证实。相比之下，CBs对人类的镇痛作用一直不可靠。临床前和临床结果之间的差异可能与过度依赖临床前研究对测量疼痛刺激行为的分析有关，疼痛刺激行为被定义为在传递有害刺激后频率和/或强度增加的行为。这些试验中的抗痛觉性表现为疼痛刺激行为的减少，这可能是由于对有害刺激的感觉敏感性降低（即真正的镇痛）或假阳性运动损伤造成的。这一应用表明，疼痛刺激行为的临床前分析容易受到与脊髓灰质炎诱发的运动损伤相关的假阳性效应的影响，从而高估了脊髓灰质炎镇痛效果。我们建议通过在一项新的疼痛抑制行为分析中评估CBs的影响来解决这一弱点。疼痛抑制行为的测试评估在传递有害刺激后，行为的速率和/或强度下降，这些测试中的抗痛觉性表现为行为的增加。这一特征使得疼痛抑制行为的检测对假阳性运动损伤不敏感。此外，疼痛抑郁行为的测定模型与临床疼痛相关的功能障碍和抑郁情绪有关。在一个例子中，杠杆按压颅内自我刺激（ICSS）在分娩后被抑制

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.