GIDP in Neuroscience, University of Arizona, Tucson, AZ, USA.
Department of Pharmacology, University of Arizona, Tucson, AZ, USA. Dr. De Felice is now with the School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom.
Pain. 2018 May;159(5):919-928. doi: 10.1097/j.pain.0000000000001167.
The response of diffuse noxious inhibitory controls (DNIC) is often decreased, or lost, in stress-related functional pain syndromes. Because the dynorphin/kappa opioid receptor (KOR) pathway is activated by stress, we determined its role in DNIC using a model of stress-induced functional pain. Male, Sprague-Dawley rats were primed for 7 days with systemic morphine resulting in opioid-induced hyperalgesia. Fourteen days after priming, when hyperalgesia was resolved, rats were exposed to environmental stress and DNIC was evaluated by measuring hind paw response threshold to noxious pressure (test stimulus) after capsaicin injection in the forepaw (conditioning stimulus). Morphine priming without stress did not alter DNIC. However, stress produced a loss of DNIC in morphine-primed rats in both hind paws that was abolished by systemic administration of the KOR antagonist, nor-binaltorphimine (nor-BNI). Microinjection of nor-BNI into the right, but not left, central nucleus of the amygdala (CeA) prevented the loss of DNIC in morphine-primed rats. Diffuse noxious inhibitory controls were not modulated by bilateral nor-BNI in the rostral ventromedial medulla. Stress increased dynorphin content in both the left and right CeA of primed rats, reaching significance only in the right CeA; no change was observed in the rostral ventromedial medulla or hypothalamus. Although morphine priming alone is not sufficient to influence DNIC, it establishes a state of latent sensitization that amplifies the consequences of stress. After priming, stress-induced dynorphin/KOR signaling from the right CeA inhibits DNIC in both hind paws, likely reflecting enhanced descending facilitation that masks descending inhibition. Kappa opioid receptor antagonists may provide a new therapeutic strategy for stress-related functional pain disorders.
伤害性刺激的扩散性抑制控制（DNIC）反应在应激相关的功能性疼痛综合征中常常减弱或消失。由于强啡肽/κ 阿片受体（KOR）途径受到应激的激活，我们通过应激诱导的功能性疼痛模型来确定其在 DNIC 中的作用。雄性 Sprague-Dawley 大鼠用全身吗啡进行 7 天的预处理，导致阿片类药物诱导的痛觉过敏。在预处理后 14 天，当痛觉过敏得到解决时，将大鼠暴露于环境应激下，并通过在前脚掌注射辣椒素（条件刺激）后测量后脚掌对有害压力的反应阈值来评估 DNIC。没有应激的吗啡预处理不会改变 DNIC。然而，应激导致吗啡预处理大鼠双侧后脚掌的 DNIC 丧失，而系统给予 KOR 拮抗剂诺比那肽（nor-BNI）则消除了这种丧失。将 nor-BNI 微注射到右侧而不是左侧杏仁中央核（CeA）中，可防止吗啡预处理大鼠的 DNIC 丧失。双侧 nor-BNI 在延髓头端腹内侧核中均不调节 DNIC。应激增加了预处理大鼠左右 CeA 中的强啡肽含量，但仅在右侧 CeA 中达到显著水平；在延髓头端腹内侧核或下丘脑未观察到变化。虽然单独的吗啡预处理不足以影响 DNIC，但它会建立一种潜在的敏化状态，放大应激的后果。在预处理后，来自右侧 CeA 的应激诱导的强啡肽/KOR 信号抑制双侧后脚掌的 DNIC，可能反映了增强的下行易化，掩盖了下行抑制。κ 阿片受体拮抗剂可能为应激相关的功能性疼痛障碍提供新的治疗策略。
