Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids
Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids
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DOI：
10.1038/npp.2013.236
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发表时间：
2014-02-01
影响因子：
7.6
通讯作者：
Negus, Stevens
中科院分区：
文献类型：
--
作者：
Leitl, Michael D.;Onvani, Sara;Negus, Stevens
疼痛通常与行为和情绪的抑郁有关，缓解疼痛相关的抑郁是治疗的共同目标。本研究验证了这一假设，即疼痛相关的行为抑郁是由内源性K-阿片系统的激活和随后的中脑边缘多巴胺释放的抑郁介导的。成年雄性Sprague-Dawley大鼠植入靶向内侧前脑束的电极（用于颅内自我刺激（ICSS）的行为研究）或植入用于微透析测量中脑核多巴胺（NAc DA）的插管。用内脏伤害性刺激（腹腔注射稀乳酸）或外源性K-激动剂（U69593）治疗后，检查ICSS和NAc DA的变化。其他研究检查了酸和U69593效应对两种镇痛药（非甾体类药物酮洛芬和m-阿片激动剂吗啡）或κ拮抗剂norbinaltorphimine（norBNI）阻断的敏感性。还检查了酸对中皮质边缘脑区强啡肽原（PDYN）和κ-阿片受体（KORs）mRNA表达的影响。酸和U69593均抑制ICSS和细胞外NAc DA水平。酮洛芬和吗啡可阻断疼痛相关的酸效应，但norBNI不能阻断。U69593的作用被norBNI阻断，但不能被酮洛芬阻断，并且仅被吗啡减弱。酸没有显着改变PDYN或KOR在NAc，但它产生了延迟增加PDYN在前额叶皮层。这些结果支持中脑边缘DA系统的关键作用，但更微妙的作用，内源性K-阿片系统，在介导急性疼痛相关的行为抑郁症大鼠。
Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This study tested the hypothesis that pain-related behavioral depression is mediated by activation of endogenous k-opioid systems and subsequent depression of mesolimbic dopamine release. Adult male Sprague-Dawley rats were implanted with electrodes targeting the medial forebrain bundle (for behavior studies of intracranial self-stimulation (ICSS)) or with cannulae for microdialysis measures of nucleus accumbens dopamine (NAc DA). Changes in ICSS and NAc DA were examined after treatment with a visceral noxious stimulus (intraperitoneal injection of dilute lactic acid) or an exogenous k-agonist (U69593). Additional studies examined the sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the m-opioid agonist morphine) or by the kappa-antagonist norbinaltorphimine (norBNI). The effects of acid were also examined on mRNA expression for prodynorphin (PDYN) and kappa-opioid receptors (KORs) in mesocorticolimbic brain regions. Both acid and U69593 depressed ICSS and extracellular levels of NAc DA. Pain-related acid effects were blocked by ketoprofen and morphine but not by norBNI. The U69593 effects were blocked by norBNI but not by ketoprofen, and were only attenuated by morphine. Acid did not significantly alter PDYN or KOR in NAc, but it produced a delayed increase in PDYN in prefrontal cortex. These results support a key role for the mesolimbic DA system, but a more nuanced role for endogenous k-opioid systems, in mediating acute pain-related behavioral depression in rats.