Optoid Analgesics: Modulation of Trigeminal & Spinal Glial Activation

描述（由申请人提供）：慢性疼痛，包括慢性口面部疼痛，在大量患者中仍然无法成功治疗。此外，长期施用一线镇痛药物如吗啡会丧失镇痛功效，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（IL-1）和白细胞介素-6（IL-6）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，即临床相关阿片类镇痛药引起的神经胶质激活可能范围广泛，而不是仅限于吗啡的现象。因此，（a）临床疼痛控制目前可能受到阿片类药物诱导的神经胶质激活的阻碍，（B）如果这是真的，那么通过寻找方法来预防或规避阿片类镇痛药引起的神经胶质激活的影响，可以改善临床疼痛控制。因此，该提案的目的是确定：（I）临床相关的阿片类镇痛剂通常是否在正常（假手术）和/或神经性（慢性压迫性损伤; CCI）疼痛状况下在三叉神经核中以及在脊髓中诱导促炎性细胞因子。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作用。还将探索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)吗啡和其它阿片样物质对脊髓促炎细胞因子的诱导部分地通过它们共同的活性代谢物（M6 G或M3 G）的作用介导;和（III）由阿片样物质药物治疗诱导的三叉神经和脊髓促炎细胞因子的产生/释放的增加通过经典阿片样物质受体介导。此外，选择性μ、δ和κ受体激动剂是否模拟临床相关镇痛剂的作用。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髓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的幅度和持续时间以缓解正常和神经性疼痛的手段的潜力。如果成功，这些研究将导致开发新的辅助疗法，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。

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.