Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, United States.
Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, United States; Alcohol & Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States; Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States.
Neuroscience. 2017 Dec 16;366:1-14. doi: 10.1016/j.neuroscience.2017.09.055. Epub 2017 Oct 9.
Repeated use of opioids can lead to the development of analgesic tolerance and dependence. Additionally, chronic opioid exposure can cause a paradoxical emergence of heightened pain sensitivity to noxious stimuli, termed hyperalgesia, which may drive continued or escalated use of opioids to manage worsening pain symptoms. Opioid-induced hyperalgesia has traditionally been measured in rodents via reflex-based assays, including the von Frey method. To better model the cognitive/motivational dimension of pain in a state of opioid dependence and withdrawal, we employed a recently developed non-reflex-based method for measuring pain avoidance-like behavior in animals (mechanical conflict avoidance test). Adult male Wistar rats were administered an escalating dose regimen of morphine (opioid-dependent group) or repeated saline (control group). Morphine-dependent rats exhibited significantly greater avoidance of noxious stimuli during withdrawal. We next investigated individual relationships between pain avoidance-like behavior and alterations in protein phosphorylation in central motivation-related brain areas. We discovered that pain avoidance-like behavior was significantly correlated with alterations in phosphorylation status of protein kinases (ERK, CaMKII), transcription factors (CREB), presynaptic markers of neurotransmitter release (Synapsin), and the rate-limiting enzyme for dopamine synthesis (TH) across specific brain regions. Our findings suggest that alterations in phosphorylation events in specific brain centers may support cognitive/motivational responses to avoid pain.
阿片类药物的重复使用会导致镇痛耐受和依赖的发展。此外，慢性阿片类药物暴露会导致对有害刺激的疼痛敏感性异常升高，称为痛觉过敏，这可能导致继续或升级使用阿片类药物来控制恶化的疼痛症状。阿片类药物诱导的痛觉过敏传统上通过基于反射的测定法在啮齿动物中进行测量，包括冯弗雷方法。为了更好地模拟阿片类药物依赖和戒断状态下疼痛的认知/动机维度，我们采用了一种新开发的非基于反射的方法来测量动物的疼痛回避样行为（机械冲突回避测试）。成年雄性 Wistar 大鼠给予递增剂量的吗啡（阿片类药物依赖组）或重复盐水（对照组）。吗啡依赖组在戒断期间表现出明显更大的回避有害刺激的行为。我们接下来研究了疼痛回避样行为与中枢动机相关脑区中蛋白磷酸化改变之间的个体关系。我们发现，疼痛回避样行为与特定脑区中蛋白激酶（ERK、CaMKII）、转录因子（CREB）、神经递质释放的突触前标志物（Synapsin）和多巴胺合成的限速酶（TH）磷酸化状态的改变显著相关。我们的研究结果表明，特定脑中枢中磷酸化事件的改变可能支持对疼痛的认知/动机反应。
