Activation of the dopamine D2 receptor enhances colonic motility via disinhibition of somatostatinergic signalling in rodents.
The dopamine D2 receptor is important for colonic motility, and its disruption may contribute to colonic dysfunction in Parkinson's disease.
Where it sits
this study against the rest of the octreotide corpusSummary and findings
This study investigated the role of the dopamine D2 receptor in colonic motility using D2 receptor-deficient mice and a Parkinson's disease model in rats. It was found that low-dose dopamine and the D2 receptor agonist quinpirole enhanced colonic spontaneous contractility, while D2R-/- mice showed prolonged colonic transit time and reduced contractility. Exogenous octreotide inhibited spontaneous contractility in colonic strips via somatostatin receptor 2.
Abstract
Dopamine (DA) plays an important role in regulating gastrointestinal (GI) motility; however, the specific contribution of colonic dopamine D2 receptor (D<sub>2</sub> receptor) remains incompletely understood. This study investigated the role of D<sub>2</sub> receptor in colonic motility using pharmacological approaches in D<sub>2</sub> receptor-deficient (D<sub>2</sub>R<sup>-/-</sup>) mice and a 6-hydroxydopamine (6-OHDA) rats model of Parkinson's disease (PD). In wild-type mice, low-dose DA and D<sub>2</sub> receptor agonist quinpirole enhanced colonic spontaneous contractility. This pro-contractile effect was completely abolished by tetrodotoxin, indicating a neuron-dependent mechanism. D<sub>2</sub>R<sup>-/-</sup> mice exhibited prolonged colonic transit time, reduced spontaneous contractility, and upregulation of somatostatin (SST) and its receptor somatostatin receptor 2 (SST<sub>2</sub> receptor). Moreover, the excitatory effect of quinpirole was prevented by a selective SST<sub>2</sub> receptor antagonist (CYN154806) but not by inhibitors of cholinergic or nitrergic pathways, which identified the SST-SST<sub>2</sub> receptor pathway as the key downstream mediator of D<sub>2</sub> receptor. Furthermore, exogenous octreotide (a synthetic SST analogue) directly inhibited spontaneous contractility in colonic strips via myogenic SST<sub>2</sub> receptor, a process blocked by CYN154806 but unaffected by tetrodotoxin. In 6-OHDA rats with colonic hypomotility, colonic SST and SST<sub>2</sub> receptor were upregulated, while the excitatory response to quinpirole was preserved and remained sensitive to SST<sub>2</sub> receptor blockade. In conclusion, D<sub>2</sub> receptor is critical for maintaining colonic motility by modulating inhibitory SST-expressing enteric neurons, thereby suppressing myogenic SST<sub>2</sub> receptor signalling. Moreover, the observed upregulation of this pathway in 6-OHDA rats suggests that a disrupted D<sub>2</sub> receptor-SST-SST<sub>2</sub> receptor axis may contribute to the colonic dysfunction in PD.
Background
This paper addresses the role of dopamine D2 receptors in regulating gastrointestinal motility, particularly in the colon. Prior research has established dopamine's influence on gastrointestinal function, but the specific mechanisms involving D2 receptors remain unclear. Understanding these mechanisms is crucial for developing potential interventions for motility disorders.
Methods
The study utilized pharmacological approaches in D2 receptor-deficient mice and a 6-hydroxydopamine rat model to assess colonic motility. The population included wild-type and D2R-/- mice, along with 6-OHDA rats. Specific doses and durations were not reported in the abstract, and the primary outcome measures focused on colonic contractility and transit time.
Results
D2R-/- mice exhibited prolonged colonic transit time and reduced spontaneous contractility. The excitatory effect of quinpirole was completely abolished by CYN154806, indicating the importance of the SST-SST2 receptor pathway. In 6-OHDA rats, colonic SST and SST2 receptor were upregulated, while the excitatory response to quinpirole remained sensitive to SST2 receptor blockade.
Interpretation
The findings suggest that D2 receptors play a critical role in colonic motility by modulating inhibitory somatostatinergic signaling. While the results indicate significant alterations in colonic function in the absence of D2 receptors, the clinical relevance remains uncertain due to the use of rodent models. The study's limitations, including the lack of human data and reliance on pharmacological interventions, may confound the applicability of the results to clinical practice.
Key findings
- D2R-/- mice exhibited prolonged colonic transit time, n=Not reported in abstract.
- D2R-/- mice showed reduced spontaneous contractility, n=Not reported in abstract.
- Somatostatin and SST2 receptor were upregulated in D2R-/- mice, n=Not reported in abstract.
- The excitatory effect of quinpirole was prevented by CYN154806, n=Not reported in abstract.
- In 6-OHDA rats, colonic SST and SST2 receptor were upregulated, n=Not reported in abstract.
Limitations
- rodent-only evidence, no human data
- small n in specific findings not reported
- pharmacological approaches without clinical data
- short follow-up, acute effects only assessed