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）：慢性疼痛，包括慢性口腔面部疼痛，在大量患者中仍未成功治疗。此外，长期使用一线镇痛药物（如吗啡）会导致镇痛效果的丧失，这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可能在广泛范围内激活神经胶质，而不是局限于吗啡的现象。因此，(a)临床疼痛控制目前可能受到阿片类药物诱导的胶质细胞激活的阻碍；(b)如果这是真的，可以通过寻找方法来预防或规避阿片类镇痛药物胶质细胞激活的影响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是否在一般情况下诱导三叉神经核中的促炎细胞因子，以及在正常（假手术）和/或神经性（慢性收缩性损伤；CCI）疼痛条件下的脊髓。此外，抗炎细胞因子是否会“揭露”慢性阿片类药物给药后的镇痛。还将探讨慢性联合抗炎细胞因子慢性增强镇痛效果的可能性。（II）吗啡和其他阿片类药物对脊髓促炎细胞因子的诱导，部分是通过其共同的活性代谢物（M6G或M3G）的作用介导的；（III）阿片药物治疗诱导三叉神经和脊柱促炎细胞因子的产生/释放升高是通过经典的阿片受体介导的。此外，选择性mu， delta和kappa受体激动剂是否模拟临床相关镇痛药的作用。在可行的情况下，坐骨神经CCI将被眶下神经CCI取代，并评估口面部机械异常性痛和热痛觉过敏。总之，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的手段来缓解正常和神经性疼痛的潜力。如果成功，这些研究将导致新的辅助疗法的发展，通过控制阿片类药物诱导的胶质细胞激活的负面后果来改善临床疼痛控制。