Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
Behavioral Genetics Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
Neuropsychopharmacology. 2014 Feb;39(3):614-24. doi: 10.1038/npp.2013.236. Epub 2013 Sep 6.
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 κ-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 κ-agonist (U69593). Additional studies examined the sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the μ-opioid agonist morphine) or by the κ-antagonist norbinaltorphimine (norBNI). The effects of acid were also examined on mRNA expression for prodynorphin (PDYN) and κ-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 κ-opioid systems, in mediating acute pain-related behavioral depression in rats.
疼痛通常与行为和情绪低落有关，缓解与疼痛相关的抑郁是治疗的常见目标。本研究检验了以下假设：与疼痛相关的行为性抑郁是通过内源性 κ-阿片系统的激活以及随后中脑边缘多巴胺释放的抑制来介导的。成年雄性 Sprague-Dawley 大鼠被植入电极，以靶向内侧前脑束（用于颅内自我刺激（ICSS）的行为研究）或用于测量伏隔核多巴胺（NAc DA）的微透析导管。在用内脏疼痛刺激（腹腔内注射稀乳酸）或外源性 κ-激动剂（U69593）处理后，检查 ICSS 和 NAc DA 的变化。进一步的研究检查了酸和 U69593 作用对两种镇痛药（非甾体抗炎药酮洛芬和 μ-阿片激动剂吗啡）或 κ-拮抗剂诺宾那醇（norBNI）的敏感性。还检查了酸对中脑边缘脑区前原啡肽（PDYN）和 κ-阿片受体（KOR）mRNA 表达的影响。酸和 U69593 均降低了 ICSS 和 NAc 中 DA 的细胞外水平。酮洛芬和吗啡可阻断与疼痛相关的酸作用，但 norBNI 则不能阻断。 norBNI 可阻断 U69593 作用，但酮洛芬则不能阻断，而且仅被吗啡减弱。酸对 NAc 中的 PDYN 或 KOR 没有显著影响，但会延迟增加前额叶皮层中的 PDYN。这些结果支持中脑边缘 DA 系统在介导大鼠急性与疼痛相关的行为性抑郁中起关键作用，但内源性 κ-阿片系统则起更微妙的作用。
