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，严重阻碍了他们的康复努力 受伤后的功能。目前的治疗是不够的，但我们最近的观察表明，大麻素， 为新的治疗方法带来希望。大麻能药物的全身给药 镇痛效用由于不同的副作用，如不必要的精神变化。不过有 越来越多的人认识到内源性大麻素（ECs）的参与， 受体，通过感觉通路的下行抑制来驱动CNS疼痛调节，表明 可能的治疗途径中脑导水管周围灰质（dPAG）是EC驱动的脑电活动的关键中枢。 通过与增强的自主神经协调的下行感觉抑制介导的抗伤害感受 通过交感神经兴奋发挥作用。我们在大鼠身上的初步数据表明，EC的适应不良 dPAG中的信号传导，包括分解代谢酶脂肪酸酰胺水解酶（FAAH）的上调， EC N-花生四烯酸乙醇胺（AEA）水平的降低与慢性 神经损伤后的疼痛和自主神经功能障碍。这些发现表明，患有慢性 神经性疼痛将受益于EC信号传导的增加，特别是在dPAG中。我们建议测试 假设内源性大麻素信号传导的失调有助于从 急性至慢性神经性疼痛。拟议研究的第一个目标是确定治疗 增强EC信号传导在治疗慢性神经性疼痛中的潜力， 从急性疼痛发展为慢性疼痛为了实现这一点，我们将测试是否衰减痛觉过敏， 在体内通过FAAH抑制（特异性目标1）、正变构调节或以下的组合实现 两者（具体目标2），用于有效且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信号传导的作用位点，这是迈向未来的重要一步。 开发治疗分子的靶向递送以增加特异性和减少不良反应 后果VA致力于更好地了解疾病的原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，女性性别严重倾向于慢性疼痛， 痛苦也有令人信服的证据表明，内源性镇痛过程更多的是大麻素 女性的依赖性要比男性高。具体目标3将解决性别方面的重大健康问题 通过评估导致性别差异的机制，在慢性疼痛的诊断和治疗方面存在差距 慢性神经性疼痛的发展及其通过增强CB 1 R信号传导的治疗。

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.