Spinal Dopaminergic Projections Control the Transition to Pathological Pain Plasticity via a D1/D5-Mediated Mechanism
Spinal Dopaminergic Projections Control the Transition to Pathological Pain Plasticity via a D1/D5-Mediated Mechanism
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DOI：
10.1523/jneurosci.3481-14.2015
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发表时间：
2015-04-22
影响因子：
5.3
通讯作者：
Price, Theodore J.
中科院分区：
文献类型：
--
作者：
Kim, Ji-Young V.;Tillu, Dipti V.;Price, Theodore J.
导致慢性疼痛状态维持的机制知之甚少，但它们的阐明可能会导致对疼痛如何成为慢性以及如何逆转的新见解。我们研究了脊髓背角神经元和下行回路在可塑性中的作用，介导向病理性疼痛可塑性的转变，表明使用痛觉过敏启动存在慢性疼痛状态。我们发现，当背角神经激肽1受体阳性神经元或下降的多巴胺能神经元在痛觉过敏引发前被消融时，IL-6和角叉菜胶诱导的机械超敏反应受损，随后的前列腺素E-2（PGE（2））反应减弱。然而，当这些神经元在引发诱导后受损时，它们对PGE（2）反应没有影响，反映了引发状态下驱动可塑性的不同机制。与此形成鲜明对比的是，脊髓应用多巴胺能损伤的动物表现出完整的IL-6和角叉菜胶诱导的机械超敏反应，但随后的PGE（2）注射未能引起机械超敏反应。此外，消融脊髓投射多巴胺能神经元后，决议的IL-6或角叉菜胶诱导的反应也逆转了维护的启动，通过评估机械超敏反应和小鼠鬼脸规模。脊髓多巴胺D-1/D-5受体的药理学拮抗作用逆转了引发，而D-1/D-5激动剂仅在引发小鼠中诱导机械超敏反应。引人注目的是，在致敏动物中，D-1/D-5与茴香霉素的结合逆转了慢性疼痛状态，这与脊髓背角中的再巩固样作用一致。这些研究结果表明，下行多巴胺能神经元在维持病理性疼痛可塑性的一个新的作用。
The mechanisms that lead to the maintenance of chronic pain states are poorly understood, but their elucidation could lead to new insights into how pain becomes chronic and how it can potentially be reversed. We investigated the role of spinal dorsal horn neurons and descending circuitry in plasticity mediating a transition to pathological pain plasticity suggesting the presence of a chronic pain state using hyperalgesic priming. We found that when dorsal horn neurokinin 1 receptor-positive neurons or descending serotonergic neurons were ablated before hyperalgesic priming, IL-6- and carrageenan-induced mechanical hypersensitivity was impaired, and subsequent prostaglandin E-2 (PGE(2)) response was blunted. However, when these neurons were lesioned after the induction of priming, they had no effect on the PGE(2) response, reflecting differential mechanisms driving plasticity in a primed state. In stark contrast, animals with a spinally applied dopaminergic lesion showed intact IL-6- and carrageenan-induced mechanical hypersensitivity, but the subsequent PGE(2) injection failed to cause mechanical hypersensitivity. Moreover, ablating spinally projecting dopaminergic neurons after the resolution of the IL-6- or carrageenan-induced response also reversed the maintenance of priming as assessed through mechanical hypersensitivity and the mouse grimace scale. Pharmacological antagonism of spinal dopamine D-1/D-5 receptors reversed priming, whereas D-1/D-5 agonists induced mechanical hypersensitivity exclusively in primed mice. Strikingly, engagement of D-1/D-5 coupled with anisomycin in primed animals reversed a chronic pain state, consistent with reconsolidation-like effects in the spinal dorsal horn. These findings demonstrate a novel role for descending dopaminergic neurons in the maintenance of pathological pain plasticity.