Optoid Analgesics: Modulation of Trigeminal & Spinal Glial Activation

Optoid 镇痛药：三叉神经的调节

• 批准号: 7840785
• 负责人: LINDA WATKINS
• 金额: $ 2.12万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7840785
• 关键词: Absence of pain sensation; Acute; Address; Agonist; Analgesics; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Anus; Area; Astrocytes; Behavioral; Bilateral; Binding; Biological Assay; Brain region; Chronic; Clinical; Data; Development; Drug Delivery Systems; Equipment; Funding; Goals; Grant; Heroin; Hyperalgesia; Immune response; Injury; Interleukin-1; Interleukin-1 Receptors; Interleukin-10; Interleukin-6; Interleukins; Investigation; Laboratories; Lead; Link; Literature; Masks; Mediating; Messenger RNA; Methadone; Methodology; Microglia; Modeling; Morphine; N-Methyl-D-Aspartate Receptors; Naloxone; Nerve; Neuroglia; Neuropathy; Operative Surgical Procedures; Opioid; Opioid Analgesics; Opioid Receptor; Orofacial Pain; Pain; Pain management; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Process; Production; Proteins; Rattus; Receptor Activation; Relative (related person); Reporting; Research Design; Research Personnel; Role; Sensory; Site; Spinal; Spinal Anesthesia; Spinal Cord; Temporomandibular Joint; Testing; Thermal Hyperalgesias; Tissues; Translating; Treatment Protocols; Trigeminal Nuclei; Trigeminal System; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Withdrawal; Writing; allodynia; anakinra; behavior test; chronic constriction injury; chronic pain; clinical efficacy; clinically relevant; clinically significant; cytokine; gene therapy; improved; insight; interest; irritation; kappa opioid receptors; mechanical allodynia; morphine-3-glucuronide; morphine-6-glucuronide; nerve injury; novel; orofacial; painful neuropathy; prevent; programs; receptor; response; sciatic nerve

DESCRIPTION (provided by applicant): Chronic pain, including chronic orofacial pain, remains unsuccessfully treated in a large number of patients. Furthermore, the loss of analgesic efficacy with chronic administration of frontline analgesic drugs, such as morphine, severely limits their use. Recent data strongly suggest that spinal cord glia (astrocytes and microglia) oppose the analgesic effects of morphine, through the release of proinflammatory cytokines: tumor necrosis factor (TNF), interleukin-1 (IL1) & interleukin-6 (IL6). While as yet unexplored, this raises the possibility that glial activation by clinically relevant opioid analgesics may be broad in scope, rather than a phenomenon restricted to morphine. Therefore, (a) clinical pain control may currently be hindered by opioid-induced glial activation &, (b) if this is true, clinical pain control could be improved by finding ways to prevent or circumvent the effects of glial activation by opioid analgesics. Therefore, the aims of the proposal are to determine whether: (I) clinically relevant opioid analgesics, in general, induce proinflammatory cytokines in trigeminal nuclei, and also in spinal cord under normal (sham) &/or neuropathic (chronic constriction injury; CCI) pain conditions. Further, whether an anti-inflammatory cytokine will "unmask" analgesia following chronic opioid administration. The potential for chronically enhancing analgesic efficacy by chronic co-administration of an anti-inflammatory cytokine will also be explored. (II) the induction of spinal proinflammatory cytokines by morphine & other opioids is mediated, in part, via actions of their common, active metabolites (M6G or M3G); and (III) the elevated production/release of trigeminal and spinal proinflammatory cytokines induced by opioid pharmacotherapies is mediated via classical opioid receptors. Moreover, whether selective mu, delta & kappa receptor agonists mimic the effects of clinically relevant analgesics. Where feasible, sciatic CCI will be replaced by CCI of the infraorbital nerve & assessment of orofacial mechanical allodynia & thermal hyperalgesia. Together these studies will provide novel insights into the actions of opioid analgesics at both trigeminal & spinal sites, & will explore the potential for using anti-inflammatory cytokines as a means of potentiating the magnitude & duration of analgesia to relieve normal & neuropathic pain. If successful, these studies will lead to development of novel adjunct therapies for improving clinical pain control by controlling the negative consequences of opioid-induced glial activation.

描述（由申请人提供）：大量患者的慢性疼痛，包括慢性口面部疼痛，仍未得到成功治疗。此外，长期服用吗啡等一线镇痛药物会丧失镇痛功效，严重限制了它们的使用。最近的数据强烈表明，脊髓胶质细胞（星形胶质细胞和小胶质细胞）通过释放促炎细胞因子：肿瘤坏死因子（TNF）、白细胞介素-1（IL1）和白细胞介素-6（IL6）来对抗吗啡的镇痛作用。虽然尚未探索，但这提出了一种可能性，即临床相关的阿片类镇痛药激活神经胶质细胞的范围可能很广泛，而不是仅限于吗啡的现象。因此，（a）目前阿片类药物诱导的神经胶质细胞活化可能阻碍临床疼痛控制，（b）如果这是真的，则可以通过寻找预防或规避阿片类镇痛药神经胶质细胞活化作用的方法来改善临床疼痛控制。因此，该提案的目的是确定：（I）临床相关的阿片类镇痛药通常会在正常（假手术）和/或神经性（慢性压迫性损伤；CCI）疼痛条件下诱导三叉神经核中以及脊髓中的促炎细胞因子。此外，抗炎细胞因子是否会“揭露”长期阿片类药物给药后的镇痛作用。还将探讨通过长期共同施用抗炎细胞因子来长期增强镇痛功效的潜力。 (II) 吗啡和其他阿片类药物诱导脊髓促炎细胞因子部分是通过其常见的活性代谢物（M6G 或 M3G）的作用介导的； (III)阿片类药物疗法诱导的三叉神经和脊髓促炎细胞因子的产生/释放增加是通过经典阿片类受体介导的。此外，选择性 mu、δ 和 kappa 受体激动剂是否模拟临床相关镇痛药的效果。在可行的情况下，坐骨 CCI 将被眶下神经 CCI 取代，并评估口面部机械异常性疼痛和热痛觉过敏。这些研究将为阿片类镇痛药在三叉神经和脊柱部位的作用提供新的见解，并将探索使用抗炎细胞因子作为增强镇痛强度和持续时间以缓解正常疼痛和神经性疼痛的方法的潜力。如果成功，这些研究将导致新型辅助疗法的开发，通过控制阿片类药物诱导的神经胶质激活的负面后果来改善临床疼痛控制。