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Endogenous cannabinoid signaling in the development of chronic neuropathic pain

慢性神经病理性疼痛发展中的内源性大麻素信号传导

基本信息

批准号：
10731350
负责人：
CARON DEAN-BERNHOFT
金额：
--
依托单位：
CLEMENT J. ZABLOCKI VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10731350
关键词：
Absence of pain sensation Acute Acute Pain Address Affect Affective Agonist Analgesics Anxiety Attenuated Automobile Driving Autonomic Dysfunction Behavior Behavioral Binding Binding Sites CNR1 gene Cannabinoids Central Nervous System Chemicals Chronic Data Development Diagnosis Disease Dorsal Down-Regulation Endocannabinoids Enzymes Estrogens FAAH inhibitor Female Future Gender Health Health Personnel Hyperalgesia Impairment Individual Injury Link Measures Mediating Mental Depression Microinjections Midbrain structure Nature Nerve Pain Neuropathy Opioid Pain Pain management Pathway interactions Pharmaceutical Preparations Predisposition Prevention Process Protocols documentation Public Health Rattus Regulation Rehabilitation therapy Research Priority Resolution Risk Safety Sensory Serum Sex Differences Signal Transduction Site Specificity System Testing Therapeutic Time Uncertainty United States National Institutes of Health Up-Regulation Veterans Woman Work addiction adverse outcome anandamide antagonist antinociception attenuation cannabinergic cannabinoid receptor chronic neuropathic pain chronic pain chronic pain management efficacy testing endocannabinoid signaling enzyme activity experimental study fatty acid amide hydrolase improved in vivo male midbrain central gray substance nerve damage nerve injury novel therapeutic intervention novel therapeutics pain chronification pain relief painful neuropathy pharmacologic positive allosteric modulator prevent response sex sexual dimorphism side effect targeted delivery

项目摘要

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.

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。目前的治疗方法还不够，但我们最近的观察表明大麻素有望带来新的治疗方法。大麻能药物的全身给药受到限制由于多种副作用（例如不需要的精神活性变化）而具有镇痛效用。然而，有人们越来越认识到内源性大麻素（EC）（大麻素的内源性激动剂）的参与受体，通过感觉通路的下降抑制来驱动中枢神经系统疼痛调节，表明可能的治疗途径。导水管周围灰背侧 (dPAG) 是 EC 驱动的关键中脑中心由下降的感觉抑制介导的镇痛作用，与增强的自主神经相协调通过交感神经兴奋发挥作用。我们在大鼠身上取得的有希望的初步数据表明，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) 的上调和 EC N-花生四烯酰乙醇胺 (AEA) 水平降低与慢性疾病的发生有关神经损伤后的疼痛和自主神经功能障碍。这些发现表明，患有慢性疾病的人神经性疼痛将受益于 EC 信号传导的增加，尤其是在 dPAG 中。我们建议测试假设内源性大麻素信号传导失调有助于从急性至慢性神经性疼痛。拟议研究的首要目标是确定治疗方法增强 EC 信号传导在治疗慢性神经性疼痛方面的潜力，最重要的是在预防方面具有潜力急性疼痛发展为慢性疼痛。为了实现这一目标，我们将测试痛觉过敏的减弱是否可以通过 FAAH 抑制（具体目标 1）、正向变构调节或以下方法的组合在体内实现两者（具体目标 2），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提高特异性并减少不良反应结果。 VA 致力于更好地了解该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，女性很容易患上慢性疼痛疼痛。还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程度高于男性。具体目标 3 将解决性别的重大健康问题通过评估导致性别差异的机制来发现慢性疼痛诊断和治疗方面的差距慢性神经性疼痛的发展及其通过增强 CB1R 信号传导的治疗。