Aversive emotion of opioid withdrawal generates motivational state leading to compulsive drug seeking and taking. Kappa opioid receptor (KOR) and its endogenous ligand dynorphin have been shown to participate in the regulation of aversive emotion. In the present study, we investigated the role of dynorphin/KOR system in the aversive emotion following opioid withdrawal in acute morphine-dependent mice. We found that blockade of KORs before pairing by intracerebroventricular injection of KOR antagonist norBNI (20, 40 μg) attenuated the development of morphine withdrawal-induced conditioned place aversion (CPA) behavior. We further found that morphine withdrawal increased dynorphin A expression in the dorsal hippocampus, but not in the amygdala, prefrontal cortex, nucleus accumbens, and thalamus. Microinjection of norBNI (20 μg) into the dorsal hippocampus significantly decreased morphine withdrawal-induced CPA behavior. We further found that p38 MAPK was significantly activated in the dorsal hippocampus after morphine withdrawal, and the activation of p38 MAPK was blocked by pretreatment with norBNI. Accordingly, microinjection of p38 MAPK inhibitor SB203580 (5 μg) into the dorsal hippocampus significantly decreased morphine withdrawal-produced CPA behavior. This study demonstrates that upregulation of dynorphin/KOR system in the dorsal hippocampus plays a critical role in the formation of aversive emotion associated with morphine withdrawal, suggesting that KOR antagonists may have therapeutic value for the treatment of opioid withdrawal-induced mood-related disorders.

阿片类药物戒断的厌恶情绪会产生动机状态，导致强迫性寻求和服用药物。 Kappa 阿片受体 (KOR) 及其内源性配体强啡肽已被证明参与厌恶情绪的调节。在本研究中，我们研究了强啡肽/KOR 系统在急性吗啡依赖小鼠阿片类药物戒断后厌恶情绪中的作用。我们发现，在配对前通过脑室内注射 KOR 拮抗剂norBNI（20、40 μg）阻断 KOR 可减弱吗啡戒断诱导的条件性位置厌恶（CPA）行为的发展。我们进一步发现，吗啡戒断会增加背侧海马中强啡肽 A 的表达，但不会增加杏仁核、前额皮质、伏核和丘脑中的强啡肽 A 表达。将norBNI (20 μg) 微量注射到背侧海马可显着降低吗啡戒断诱导的CPA 行为。我们进一步发现吗啡戒断后背侧海马p38 MAPK显着激活，并且用norBNI预处理可阻断p38 MAPK的激活。因此，将 p38 MAPK 抑制剂 SB203580 (5 μg) 显微注射到背侧海马可显着降低吗啡戒断引起的 CPA 行为。这项研究表明，背侧海马强啡肽/KOR系统的上调在与吗啡戒断相关的厌恶情绪的形成中起着关键作用，这表明KOR拮抗剂可能对治疗阿片类药物戒断引起的情绪相关疾病具有治疗价值。