Departments of Chemistry and Biochemistry, and.
Pharmacology, University of Arizona, Tucson, AZ, United States.
Pain. 2020 Oct;161(10):2376-2384. doi: 10.1097/j.pain.0000000000001925.
Diseases and disorders such as Parkinson disease, schizophrenia, and chronic pain are characterized by altered mesolimbic dopaminergic neurotransmission. Dopamine release in the nucleus accumbens influences behavior through both tonic and phasic signaling. Tonic dopamine levels are hypothesized to inversely regulate phasic signals through dopamine D2 receptor feedback inhibition. We tested this hypothesis directly in the context of ongoing pain. Tonic and phasic dopamine signals were measured using fast-scan controlled-adsorption voltammetry and fast-scan cyclic voltammetry, respectively, in the nucleus accumbens shell of male rats with standardized levels of anesthesia. Application of capsaicin to the cornea produced a transient decrease in tonic dopamine levels. During the pain-induced hypodopaminergic state, electrically evoked phasic dopamine release was significantly increased when compared to baseline, evoked phasic release. A second application of capsaicin to the same eye had a lessened effect on tonic dopamine suggesting desensitization of TRPV1 channels in that eye. Capsaicin treatment in the alternate cornea, however, again produced coincident decreased dopaminergic tone and increased phasic dopamine release. These findings occurred independently of stimulus lateralization relative to the hemisphere of dopamine measurement. Our data show that (1) the mesolimbic dopamine circuit reliably encodes acute noxious stimuli; (2) ongoing pain produces decreases in dopaminergic tone; and (3) pain-induced decreases in tonic dopamine correspond to augmented evoked phasic dopamine release. Enhanced phasic dopamine neurotransmission resulting from salient stimuli may contribute to increased impulsivity and cognitive deficits often observed in conditions associated with decreased dopaminergic tone, including Parkinson disease and chronic pain.
帕金森病、精神分裂症和慢性疼痛等疾病和障碍的特征是中脑边缘多巴胺能神经传递的改变。伏隔核中的多巴胺释放通过紧张和相位信号影响行为。紧张型多巴胺水平被假设通过多巴胺 D2 受体反馈抑制来反向调节相位信号。我们在持续疼痛的背景下直接测试了这一假设。使用快速扫描控制吸附伏安法和快速扫描循环伏安法分别测量伏隔核壳中的紧张型和相位型多巴胺信号，雄性大鼠的麻醉水平标准化。将辣椒素应用于角膜会导致紧张型多巴胺水平短暂下降。在疼痛引起的低多巴胺状态下，与基线相比，电诱发的相位多巴胺释放显著增加，诱发的相位释放。对同一只眼睛再次应用辣椒素对紧张型多巴胺的作用减弱，表明该眼中 TRPV1 通道脱敏。然而，在另一只角膜中给予辣椒素治疗再次产生了一致的降低多巴胺能张力和增加相位多巴胺释放。这些发现与相对于多巴胺测量半球的刺激侧化无关。我们的数据表明：（1）中脑边缘多巴胺回路可靠地编码急性伤害性刺激；（2）持续疼痛会导致多巴胺能张力降低；（3）紧张型多巴胺的减少与诱发的相位多巴胺释放增加相对应。由于显著刺激而增强的相位多巴胺神经传递可能导致冲动性增加和认知缺陷，这些缺陷经常在与多巴胺能张力降低相关的疾病中观察到，包括帕金森病和慢性疼痛。
