Crain Stanley M, Shen Ke-Fei
Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Brain Res. 2008 Sep 22;1231:16-24. doi: 10.1016/j.brainres.2008.07.015. Epub 2008 Jul 12.
Systemic (s.c.) injection in naïve mice of cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitors, e.g. 3-isobutyl-1-methylxanthine [(IBMX) or caffeine, 10 mg/kg] or the more specific cAMP-PDE inhibitor, rolipram (1 mug/kg), rapidly evokes thermal hyperalgesia (lasting >5 h). These effects appear to be mediated by enhanced excitatory opioid receptor signaling, as occurs during withdrawal in opioid-dependent mice. Cotreatment of these mice with ultra-low-dose naltrexone (NTX, 0.1 ng/kg-1 pg/kg, s.c.) results in prominent opioid analgesia (lasting >4 h) even when the dose of rolipram is reduced to 1 pg/kg. Cotreatment of these cAMP-PDE inhibitors in naïve mice with an ultra-low-dose (0.1 ng/kg) of the kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI) or the mu-opioid receptor antagonist, beta-funaltrexamine (beta-FNA) also results in opioid analgesia. These excitatory effects of cAMP-PDE inhibitors in naïve mice may be mediated by enhanced release of small amounts of endogenous bimodally-acting (excitatory/inhibitory) opioid agonists by neurons in nociceptive networks. Ultra-low-dose NTX, nor-BNI or beta-FNA selectively antagonizes high-efficacy excitatory (hyperalgesic) Gs-coupled opioid receptor-mediated signaling in naïve mice and results in rapid conversion to inhibitory (analgesic) Gi/Go-coupled opioid receptor-mediated signaling which normally requires activation by much higher doses of opioid agonists. Cotreatment with a low subanalgesic dose of kelatorphan, an inhibitor of multiple endogenous opioid peptide-degrading enzymes, stabilizes endogenous opioid agonists released by cAMP-PDE inhibitors, resulting in conversion of the hyperalgesia to analgesia without requiring selective blockade of excitatory opioid receptor signaling. The present study provides a novel pharmacologic paradigm that may facilitate development of valuable non-narcotic clinical analgesics utilizing cotreatment with ultra-low-dose rolipram plus ultra-low-dose NTX or related agents.
在未经处理的小鼠中全身（皮下）注射环磷酸腺苷磷酸二酯酶（cAMP-PDE）抑制剂，如3-异丁基-1-甲基黄嘌呤[（IBMX）或咖啡因，10毫克/千克]或更具特异性的cAMP-PDE抑制剂咯利普兰（1微克/千克），会迅速引发热痛觉过敏（持续>5小时）。这些效应似乎是由增强的兴奋性阿片受体信号传导介导的，就像阿片依赖小鼠戒断期间发生的那样。用超低剂量纳曲酮（NTX，0.1纳克/千克 - 1皮克/千克，皮下注射）对这些小鼠进行联合治疗，即使将咯利普兰的剂量降至1皮克/千克，也会产生显著的阿片类镇痛作用（持续>4小时）。在未经处理的小鼠中，用超低剂量（0.1纳克/千克）的κ-阿片受体拮抗剂诺-宾丙诺啡（nor-BNI）或μ-阿片受体拮抗剂β-芬太尼胺（β-FNA）与这些cAMP-PDE抑制剂进行联合治疗，也会产生阿片类镇痛作用。cAMP-PDE抑制剂在未经处理的小鼠中的这些兴奋作用可能是由伤害性感受网络中的神经元增强释放少量具有双相作用（兴奋性/抑制性）的内源性阿片类激动剂介导的。超低剂量的NTX、nor-BNI或β-FNA选择性拮抗未经处理的小鼠中高效兴奋性（痛觉过敏）Gs偶联阿片受体介导的信号传导，并导致迅速转变为抑制性（镇痛）Gi/Go偶联阿片受体介导的信号传导，而这种信号传导通常需要更高剂量的阿片类激动剂激活。用低剂量亚镇痛剂量的凯拉托芬（一种多种内源性阿片肽降解酶的抑制剂）进行联合治疗，可稳定cAMP-PDE抑制剂释放的内源性阿片类激动剂，从而在不需要选择性阻断兴奋性阿片受体信号传导的情况下将痛觉过敏转变为镇痛。本研究提供了一种新的药理学模式，可能有助于开发利用超低剂量咯利普兰加超低剂量NTX或相关药物联合治疗的有价值的非麻醉性临床镇痛药。
