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，包括慢性口腔疼痛，在大量患者中仍未成功治疗。此外，长期施用前线镇痛药（例如吗啡）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的释放反对吗啡的镇痛作用：肿瘤坏死因子（TNF），白介素-1（IL1）（IL1）＆interleuukin-6（iLL6）（IL6）。尽管尚未探索，但这增加了临床相关的阿片类镇痛药的神经胶质激活的可能性，而不是局限于吗啡的现象。因此，（a）目前可能会通过阿片类药物诱导的神经胶质激活而阻碍临床疼痛控制，（b）如果这是真的，则可以通过寻找预防或避免阿片类镇痛药的胶质激活作用来改善临床疼痛控制。因此，该提案的目的是确定：（i）通常在三叉神经核中诱导促炎性细胞因子，以及在正常（假）和/或神经病变（慢性狭窄损伤; CCI）疼痛条件下诱导促炎性细胞因子。此外，慢性阿片类药物给药后，抗炎细胞因子是否会“揭露”镇痛。还将探索抗炎细胞因子的慢性共同给药，从而慢性增强镇痛功效的潜力。 （ii）吗啡和其他阿片类药物诱导脊柱促炎细胞因子的诱导是通过其共同的活性代谢产物（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柱促炎细胞因子的产生/释放升高是通过经典阿片类受体介导的。此外，选择性MU，Delta和Kappa受体激动剂是否模仿临床相关的镇痛药的影响。在可行的情况下，坐骨神经CCI将被胸骨神经的CCI取代，并评估了口腔机械性异常和热痛觉过敏的评估。这些研究将共同​​提供对阿片类镇痛药在三叉神经和脊柱部位的作用的新颖见解，并且将探索使用抗炎细胞因子作为增强镇痛的幅度和镇痛持续时间来缓解正常和神经性疼痛的潜力。如果成功，这些研究将通过控制阿片类药物诱导的神经胶质激活的负面后果来发展新型辅助疗法，以改善临床疼痛控制。