Koo Ho, Wang Jigong, Pariyar Ramesh, Hammond Regan M, La Jun-Ho
Department of Neurobiology, University of Texas Medical Branch, Galveston, TX, USA.
Pain Rep. 2024 Sep 10;9(5):e1186. doi: 10.1097/PR9.0000000000001186. eCollection 2024 Oct.
The lateral parabrachial nucleus (LPBN), a crucial hub for integrating and modulating diverse sensory information, is known to express both D1 and D2 dopamine receptors and receive dopaminergic inputs. However, the role of the LPBN's dopaminergic system in somatosensory processing remains largely unexplored. In this study, we investigated whether mechanical sensory stimulation triggers dopamine release in the LPBN and how D1- and D2-like receptor signaling in the LPBN influences mechanosensitivity in mice.
We used a G-protein-coupled receptor-based dopamine sensor to monitor dopamine release in the LPBN and a von Frey filament assay to measure the mechanical threshold for nocifensive withdrawal in mouse hind paws after unilateral microinjection of D1- or D2-like receptor antagonist into the LPBN.
Noxious mechanical stimulation increased the dopamine sensor signal in the LPBN. Thresholds of nocifensive withdrawal from mechanical stimulation were decreased by the D1-like receptor antagonist SCH-23390 (0.1 µg) but increased by the D2-like receptor antagonist eticlopride (1 µg). In the intraplantar capsaicin injection model that develops mechanical hypersensitivity in the injected paw, the dopamine sensor signal in the LPBN was increased, and eticlopride (1 µg) in the LPBN significantly inhibited the capsaicin-induced mechanical hypersensitivity.
These results suggest that endogenous dopaminergic signaling occurs in the LPBN upon noxious mechanical stimulation, inhibiting mechanosensitivity through D1-like receptors while enhancing it through D2-like receptors. D2-like receptor signaling in the LPBN may contribute to an injury-induced increase in mechanical nociception, indicating that inhibiting the receptor within the LPBN could offer potential as a novel analgesic strategy.
外侧臂旁核（LPBN）是整合和调节多种感觉信息的关键枢纽，已知其表达D1和D2多巴胺受体并接受多巴胺能输入。然而，LPBN多巴胺能系统在躯体感觉处理中的作用在很大程度上仍未得到探索。在本研究中，我们调查了机械感觉刺激是否会触发LPBN中的多巴胺释放，以及LPBN中的D1样和D2样受体信号如何影响小鼠的机械敏感性。
我们使用基于G蛋白偶联受体的多巴胺传感器来监测LPBN中的多巴胺释放，并使用von Frey细丝试验来测量在向LPBN单侧微量注射D1样或D2样受体拮抗剂后小鼠后爪伤害性退缩的机械阈值。
有害机械刺激增加了LPBN中的多巴胺传感器信号。D1样受体拮抗剂SCH-23390（0.1μg）降低了对机械刺激的伤害性退缩阈值，但D2样受体拮抗剂依替必利（1μg）则使其升高。在足底注射辣椒素后在注射爪产生机械超敏反应的模型中，LPBN中的多巴胺传感器信号增加，并且LPBN中的依替必利（1μg）显著抑制了辣椒素诱导的机械超敏反应。
这些结果表明，有害机械刺激时LPBN中会发生内源性多巴胺能信号传导，通过D1样受体抑制机械敏感性，同时通过D2样受体增强机械敏感性。LPBN中的D2样受体信号可能导致损伤诱导的机械性伤害感受增加，这表明抑制LPBN内的该受体可能具有作为新型镇痛策略的潜力。
