Zhang Yong, Schalo Ian, Durand Cindy, Standifer Kelly M
Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
Front Psychiatry. 2019 Jan 8;9:731. doi: 10.3389/fpsyt.2018.00731. eCollection 2018.
Nociceptin/Orphanin FQ (N/OFQ) is a neuropeptide that modulates pain transmission, learning/memory, stress, anxiety, and fear responses via activation of the N/OFQ peptide (NOP or ORL1) receptor. Post-traumatic stress disorder (PTSD) is an anxiety disorder that may arise after exposure to a traumatic or fearful event, and often is co-morbid with chronic pain. Using an established animal model of PTSD, single-prolonged stress (SPS), we were the first to report that NOP receptor antagonist treatment reversed traumatic stress-induced allodynia, thermal hyperalgesia, and anxiety-like behaviors in male Sprague-Dawley rats. NOP antagonist treatment also reversed SPS-induced serum and CSF N/OFQ increase and circulating corticosterone decrease. The objective of this study was to examine the role of the NOP receptor in male and female rats subjected to traumatic stress using Wistar wild type (WT) and NOP receptor knockout (KO) rats. The severity of co-morbid allodynia was assessed as change in paw withdrawal threshold (PWT) to von Frey and paw withdrawal latency (PWL) to radiant heat stimuli, respectively. PWT and PWL decreased in male and female WT rats within 7 days after SPS, and remained decreased through day 28. Baseline sensitivity did not differ between genotypes. However, while male NOP receptor KO rats were protected from SPS-induced allodynia and thermal hypersensitivity, female NOP receptor KO rats exhibited tactile allodynia and thermal hypersensitivity to the same extent as WT rats. Male NOP receptor KO rats had a lower anxiety index (AI) than WT, but SPS did not increase AI in WT males. In contrast, SPS significantly increased AI in WT and NOP receptor KO female rats. SPS increased circulating N/OFQ levels in male WT, but not in male NOP receptor KO, or WT or KO female rats. These results indicate that the absence of the NOP receptor protects males from traumatic-stress-induced allodynia and hyperalgesia, consistent with our previous findings utilizing a NOP receptor antagonist. However, female NOP receptor KO rats experience allodynia, hyperalgesia and anxiety-like symptoms to the same extent as WT females following SPS. This suggests that endogenous N/OFQ-NOP receptor signaling plays an important, but distinct, role in males and females following exposure to traumatic stress.
痛敏肽/孤啡肽FQ（N/OFQ）是一种神经肽，它通过激活N/OFQ肽（NOP或ORL1）受体来调节疼痛传递、学习/记忆、应激、焦虑和恐惧反应。创伤后应激障碍（PTSD）是一种焦虑症，可能在接触创伤性或恐惧性事件后出现，并且常常与慢性疼痛共病。使用一种已建立的创伤后应激障碍动物模型，即单次长时间应激（SPS），我们首次报道NOP受体拮抗剂治疗可逆转雄性Sprague-Dawley大鼠创伤应激诱导的痛觉过敏、热痛觉过敏和焦虑样行为。NOP拮抗剂治疗还可逆转SPS诱导的血清和脑脊液中N/OFQ升高以及循环皮质酮降低。本研究的目的是使用Wistar野生型（WT）和NOP受体敲除（KO）大鼠，研究NOP受体在遭受创伤应激的雄性和雌性大鼠中的作用。共病性痛觉过敏的严重程度分别通过对von Frey刺激的爪撤离阈值（PWT）变化和对热辐射刺激的爪撤离潜伏期（PWL）变化来评估。SPS后7天内，雄性和雌性WT大鼠的PWT和PWL均降低，并持续到第28天。不同基因型的基线敏感性无差异。然而，虽然雄性NOP受体KO大鼠免受SPS诱导的痛觉过敏和热超敏反应，但雌性NOP受体KO大鼠表现出与WT大鼠相同程度的触觉痛觉过敏和热超敏反应。雄性NOP受体KO大鼠的焦虑指数（AI）低于WT大鼠，但SPS并未增加WT雄性大鼠的AI。相比之下，SPS显著增加了WT和NOP受体KO雌性大鼠的AI。SPS使雄性WT大鼠循环N/OFQ水平升高，但雄性NOP受体KO大鼠、WT或KO雌性大鼠则未升高。这些结果表明，NOP受体的缺失可保护雄性大鼠免受创伤应激诱导的痛觉过敏和痛觉超敏反应，这与我们之前使用NOP受体拮抗剂的研究结果一致。然而，雌性NOP受体KO大鼠在SPS后与WT雌性大鼠经历相同程度的痛觉过敏、痛觉超敏反应和焦虑样症状。这表明内源性N/OFQ-NOP受体信号在雄性和雌性大鼠遭受创伤应激后发挥重要但不同的作用。
