Endogenous cannabinoid signaling in the development of chronic neuropathic pain

神经性疼痛是退伍军人中的一个常见问题，严重阻碍了他们康复的努力 损伤后的功能。目前的治疗方法是不够的，但我们最近的观察表明，大麻类药物 为新的治疗方法保有希望。大麻能药物的全身性给药受到限制 由于不同的副作用而产生的止痛效用，如不想要的精神活性改变。然而，还有 越来越多的人认识到内源性大麻素激动剂--内源性大麻素的参与 受体通过感觉通路的下行抑制来驱动中枢神经系统的痛觉调节，表明 可能的治疗途径。中脑导水管周围灰质背侧(DPAG)是EC驱动的关键中脑中枢 下行感觉抑制与增强的自主神经协同介导的抗伤害性感觉 通过交感神经兴奋起作用。我们在大鼠身上有希望的初步数据表明，EC的适应不良 DPAG中的信号，包括分解代谢酶脂肪酸酰胺水解酶(FAAH)的上调和 EC N-花生四烯基乙醇胺(AEA)水平降低与慢性 神经损伤后疼痛和自主神经功能障碍。这些发现表明，患有慢性病的人 神经病理性疼痛将受益于EC信号的增加，特别是在DPAG。我们建议测试一下 假设内源性大麻素信号的失调有助于从 急性到慢性神经病理性疼痛。拟议研究的第一个目标是确定治疗方法 增强的EC信号在治疗慢性神经病理性疼痛中的潜力，更重要的是，在预防 急性疼痛进展为慢性疼痛。为了实现这一点，我们将测试痛觉过敏的衰减是否可以 通过抑制FAAH(特定目标1)、正变构调节或以下两者的组合在体内实现 两者(具体目标2)，用于有效和安全地预防或治疗慢性神经性疼痛。这些目标 将评估DPAG作为增强EC信令的行动地点，这是迈向未来的关键一步 开发靶向递送治疗分子以提高特异性和减少不良反应 后果。退伍军人管理局致力于更好地了解该病的病因和潜在的治疗方法。 女性退伍军人的慢性疼痛，因为毫无疑问，女性的性行为极易患上慢性 疼痛。也有令人信服的证据表明，内源性止痛过程更多的是大麻素 对女性的依赖大于对男性的依赖。具体目标3将解决两性对健康的重大关切 通过评估慢性疼痛的性别差异在诊断和治疗方面的差距 慢性神经病理性疼痛的发展及其通过增强CB1R信号的治疗。

Neuropathic pain is a common problem among Veterans that substantially impedes their efforts to rehabilitate function following injury. Current treatments are inadequate, but our recent observations show that cannabinoids hold promise for new therapeutic approaches. Systemic administration of cannabinergic drugs has limited analgesic utility due to diverse side effects, such as unwanted psychoactive changes. However, there is growing recognition of the participation of endocannabinoids (ECs), the endogenous agonists of cannabinoid receptors, in driving CNS pain regulation through descending inhibition of sensory pathways, indicating a possible avenue for therapy. The dorsal periaqueductal gray (dPAG) is a key midbrain center for EC-driven antinociception mediated by descending sensory inhibition that is coordinated with enhanced autonomic function through sympathoexcitation. Our promising preliminary data in rats show that maladaptations of EC signaling in the dPAG, including upregulation of the catabolic enzyme fatty acid amide hydrolase (FAAH) and reduced levels of the EC N-arachidonoylethanolamine (AEA), are associated with the development of chronic pain and autonomic dysfunction after nerve injury. These findings suggest that individuals who develop chronic neuropathic pain would benefit from increased EC signaling, particularly in the dPAG. We propose to test the hypothesis that dysregulation of endogenous cannabinoid signaling contributes to the transition from acute to chronic neuropathic pain. The first objective of the proposed studies is to determine the therapeutic potential of enhanced EC signaling in the treatment of chronic neuropathic pain and, critically, in the prevention of acute pain progressing to chronic pain. To achieve this, we will test whether attenuation of hyperalgesia can be achieved in vivo with FAAH inhibition (Specific Aim 1), positive allosteric modulation or a combination of both (Specific Aim 2), for effective and safe prevention or treatment of chronic neuropathic pain. These aims will evaluate the dPAG as a site of action for enhanced EC signaling, which is a vital step towards future development of targeted delivery of therapeutic molecules for increased specificity and decreased adverse consequences. The VA is committed to pursuing a better understanding of causes and potential treatments of chronic pain in women veterans as there is no doubt that female sex heavily predisposes a subject to chronic pain. There is also convincing evidence that endogenous analgesic processes are more cannabinoid dependent in females than in males. Specific Aim 3 will address the significant health concern of the gender gap in the diagnosis and treatment of chronic pain by evaluating mechanisms contributing to sex differences in the development of chronic neuropathic pain and its treatment through enhanced CB1R signaling.