Optoid Analgesics: Modulation of Trigeminal & Spinal Glial Activation

描述(申请人提供)：慢性疼痛，包括慢性口腔面部疼痛，在许多患者中仍然没有得到成功的治疗。此外，长期服用一线止痛药，如吗啡，止痛效果的丧失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)通过释放促炎症细胞因子：肿瘤坏死因子(TNF)、白介素1(IL1)和白介素6(IL6)来对抗吗啡的镇痛作用。虽然尚未被探索，但这增加了一种可能性，即临床上相关的阿片类镇痛剂激活神经胶质的范围可能很广，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神经胶质激活的阻碍，(B)如果这是真的，可以通过找到防止或规避阿片类止痛剂激活神经胶质的效果的方法来改善临床疼痛控制。因此，该提案的目的是确定：(I)临床上相关的阿片类镇痛剂是否在正常(假)和/或神经病理性(慢性缩窄性损伤；CCI)疼痛条件下，在三叉神经核和脊髓中诱导促炎细胞因子。此外，抗炎细胞因子是否会揭开长期服用阿片类药物后的止痛的面纱。还将探索通过长期联合应用抗炎细胞因子来慢性增强止痛效果的可能性。(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)的作用而介导的；以及(Iii)阿片类药物治疗诱导的三叉神经和脊髓促炎细胞因子的产生/释放增加是通过经典的阿片受体介导的。此外，选择性MU、β受体和Kappa受体激动剂是否模仿临床相关止痛药的效果。在可行的情况下，坐骨神经CCI将被眶下神经CCI取代&口面部机械性痛觉异常和热痛敏的评估。总之，这些研究将为阿片类止痛剂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一种手段来增强止痛的幅度和持续时间以缓解正常和神经病理性疼痛的可能性。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.