Activation of the Dopamine D2 Receptor Enhances Colonic Motility via Disinhibition of Somatostatinergic Signalling in Rodents.

Dopamine (DA) plays an important role in regulating gastrointestinal (GI) motility; however, the specific contribution of colonic dopamine D2 receptor (D2 receptor) remains incompletely understood. This study investigated the role of D2 receptor in colonic motility using pharmacological approaches in D2 receptor-deficient (D2R-/-) mice and a 6-hydroxydopamine (6-OHDA) rats model of Parkinson's disease (PD). In wild-type mice, low-dose DA and D2 receptor agonist quinpirole enhanced colonic spontaneous contractility. This pro-contractile effect was completely abolished by tetrodotoxin, indicating a neuron-dependent mechanism. D2R-/- mice exhibited prolonged colonic transit time, reduced spontaneous contractility, and upregulation of somatostatin (SST) and its receptor somatostatin receptor 2 (SST2 receptor). Moreover, the excitatory effect of quinpirole was prevented by a selective SST2 receptor antagonist (CYN154806) but not by inhibitors of cholinergic or nitrergic pathways, which identified the SST-SST2 receptor pathway as the key downstream mediator of D2 receptor. Furthermore, exogenous octreotide (a synthetic SST analogue) directly inhibited spontaneous contractility in colonic strips via myogenic SST2 receptor, a process blocked by CYN154806 but unaffected by tetrodotoxin. In 6-OHDA rats with colonic hypomotility, colonic SST and SST2 receptor were upregulated, while the excitatory response to quinpirole was preserved and remained sensitive to SST2 receptor blockade. In conclusion, D2 receptor is critical for maintaining colonic motility by modulating inhibitory SST-expressing enteric neurons, thereby suppressing myogenic SST2 receptor signalling. Moreover, the observed upregulation of this pathway in 6-OHDA rats suggests that a disrupted D2 receptor-SST-SST2 receptor axis may contribute to the colonic dysfunction in PD.