Kato Takahiro, Ide Soichiro, Minami Masabumi
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan; Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
Neurosci Lett. 2016 Aug 26;629:73-78. doi: 10.1016/j.neulet.2016.06.060. Epub 2016 Jun 29.
Comorbidity of chronic pain and depression has long been recognized in the clinic, and preclinical studies have reported depression-like behaviors in animal models of chronic pain. These findings suggest a common neuronal basis for chronic pain and depression. The neuronal pathway from the ventral tegmental area to the nucleus accumbens (NAc) is critical in the mesolimbic dopamine (DA) reward circuit, and dysfunction of this pathway has been implicated in depression. Although time-dependent development of depression-related behaviors has been reported in chronic pain animals, time-dependent functional changes in this pathway remain to be examined. To address this issue, we examined the effects of two types of rewards, pain relief by intrathecal injection of pregabalin (100μg in 10μL phosphate buffered saline) and 30% sucrose solution intake, on intra-NAc DA release in rats subjected to spinal nerve ligation (SNL). Specifically, the effects were investigated during the early (17-20days after ligation) and late (31-34days after ligation) phases of neuropathic pain. Pain relief increased the intra-NAc DA levels in the SNL rats during the early but not late phase of neuropathic pain. Intake of the sucrose solution increased the intra-NAc DA levels both in the SNL and sham animals during the early phase of neuropathic pain, while it induced DA release in the sham but not SNL animals during the late phase. These results suggest that dysfunction of the mesolimbic DA reward circuit develops in a time-dependent manner. Mesolimbic DA reward circuit dysfunction might be a common neuronal mechanism underlying chronic pain and depression, and a potential target for novel analgesic and antidepressant medications.
慢性疼痛与抑郁症的共病现象在临床上早已得到认可，临床前研究也已报道慢性疼痛动物模型中存在类似抑郁的行为。这些发现提示慢性疼痛和抑郁症存在共同的神经基础。从腹侧被盖区到伏隔核（NAc）的神经通路在中脑边缘多巴胺（DA）奖赏回路中至关重要，该通路功能障碍与抑郁症有关。尽管已有报道称慢性疼痛动物中与抑郁相关的行为会随时间发展，但该通路随时间的功能变化仍有待研究。为解决这一问题，我们研究了鞘内注射普瑞巴林（100μg溶于10μL磷酸盐缓冲盐水中）缓解疼痛和摄入30%蔗糖溶液这两种奖赏方式对脊髓神经结扎（SNL）大鼠NAc内DA释放的影响。具体而言，在神经性疼痛的早期（结扎后17 - 20天）和晚期（结扎后31 - 34天）对这些影响进行了研究。在神经性疼痛的早期而非晚期，疼痛缓解增加了SNL大鼠NAc内的DA水平。在神经性疼痛的早期，摄入蔗糖溶液增加了SNL大鼠和假手术动物NAc内的DA水平，而在晚期，它在假手术动物中诱导了DA释放，但在SNL大鼠中未诱导。这些结果表明中脑边缘DA奖赏回路功能障碍以时间依赖的方式发展。中脑边缘DA奖赏回路功能障碍可能是慢性疼痛和抑郁症共同的神经机制，也是新型镇痛和抗抑郁药物的潜在靶点。
