Brody School of Medicine, Department of Physiology, East Carolina University, Greenville, NC 27834, USA.
Exp Neurol. 2012 Dec;238(2):273-83. doi: 10.1016/j.expneurol.2012.09.002. Epub 2012 Sep 17.
Frequency-dependent modulation and dopamine (DA) receptors strongly modulate neural circuits in the spinal cord. Of the five known DA receptor subtypes, the D3 receptor has the highest affinity to DA, and D3-mediated actions are mainly inhibitory. Using an animal model of spinal sensorimotor dysfunction, the D3 receptor knockout mouse (D3KO), we investigated the physiological consequences of D3 receptor dysfunction on pain-associated signaling pathways in the spinal cord, the initial integration site for the processing of pain signaling. In the D3KO spinal cord, inhibitory actions of DA on the proprioceptive monosynaptic stretch reflex are converted from depression to facilitation, but its effects on longer-latency and pain-associated reflex responses and the effects of FM have not been studied. Using behavioral approaches in vivo, we found that D3KO animals exhibit reduced paw withdrawal latencies to thermal pain stimulation (Hargreaves' test) over wild type (WT) controls. Electrophysiological and pharmacological approaches in the isolated spinal cord in vitro showed that constant current stimulation of dorsal roots at a pain-associated frequency was associated with a significant reduction in the frequency-dependent modulation of longer-latency reflex (LLRs) responses but not monosynaptic stretch reflexes (MSRs) in D3KO. Application of the D1 and D2 receptor agonists and the voltage-gated calcium-channel ligand, pregabalin, but not DA, was able to restore the frequency-dependent modulation of the LLR in D3KO to WT levels. Thus we demonstrate that nociception-associated LLRs and proprioceptive MSRs are differentially modulated by frequency, dopaminergics and the Ca(2+) channel ligand, pregabalin. Our data suggest a role for the DA D3 receptor in pain modulation and identify the D3KO as a possible model for increased nociception.
频率依赖性调制和多巴胺（DA）受体强烈调节脊髓中的神经回路。在已知的五种 DA 受体亚型中，D3 受体对 DA 的亲和力最高，D3 介导的作用主要是抑制性的。使用脊髓感觉运动功能障碍的动物模型，D3 受体敲除小鼠（D3KO），我们研究了 D3 受体功能障碍对脊髓中与疼痛相关的信号通路的生理后果，脊髓是疼痛信号处理的初始整合部位。在 D3KO 脊髓中，DA 对本体感受单突触牵张反射的抑制作用从抑制转变为易化，但尚未研究其对较长潜伏期和与疼痛相关的反射反应以及 FM 的影响。使用体内行为方法，我们发现 D3KO 动物对热痛刺激（Hargreaves 测试）的爪回缩潜伏期缩短，而野生型（WT）对照则缩短。在离体脊髓中的电生理和药理学方法表明，在与疼痛相关的频率下对背根进行恒定电流刺激与较长潜伏期反射（LLRs）反应的频率依赖性调制的显著减少有关，但与单突触牵张反射（MSRs）无关在 D3KO 中。D1 和 D2 受体激动剂和电压门控钙通道配体普加巴林的应用，但不是 DA，能够将 D3KO 中 LLR 的频率依赖性调制恢复到 WT 水平。因此，我们证明与伤害感受相关的 LLR 和本体感受的 MSR 受到频率、多巴胺能和钙通道配体普加巴林的差异调节。我们的数据表明 DA D3 受体在疼痛调节中起作用，并确定 D3KO 可能是疼痛增加的模型。
