Role of enteric dopaminergic neurons in regulating peristalsis of rat proximal colon

Abstract

Background Constipation is commonly seen in patients with Parkinson's disease associated with a loss of dopaminergic neurons in both central and enteric nervous systems. However, the roles of enteric dopaminergic neurons in developing constipation remain to be elucidated. Here, we investigated the roles of enteric dopaminergic neurons in the generation of colonic peristalsis. Methods Cannulated segments of rat proximal colon were situated in the organ bath, abluminally perfused with physiological salt solution and luminally perfused with 0.9% saline. Drugs were applied in the abluminal solution. Changes in diameter along the length of the colonic segment were captured by a video camera and transformed into spatio‐temporal maps. Fluorescence immunohistochemistry was also carried out. Key Results Blockade of nitrergic neurotransmission prevented oro‐aboral propagation of peristaltic waves and caused a colonic constriction without affecting ripples, non‐propagating myogenic contractions. Blockade of cholinergic neurotransmission also prevented peristaltic waves but suppressed ripples with a colonic dilatation. Tetrodotoxin (0.6 μM) abolished peristaltic waves and increased ripples with a constriction. SCH 23390 (20 μM), a D1‐like dopamine receptor antagonist, slowed the peristaltic waves and caused a constriction, while GBR 12909 (1 μM), a dopamine reuptake inhibitor, diminished the peristaltic waves with a dilatation. Bath‐applied dopamine (3 μM) abolished the peristaltic waves associated with a colonic dilation in an SCH 23390 (5 μM)‐sensitive manner. D1 receptor immunoreactivity was co‐localized to nitrergic and cholinergic neurons. Conclusions and Inferences Dopaminergic neurons appear to facilitate nitrergic neurons via D1‐like receptors to stabilize asynchronous contractile activity resulting in the generation of colonic peristalsis.

Aggregation of alpha-synuclein in enteric neurons does not impact function in vitro

“…Peristalsis is maintained through a complex excitation and inhibition pattern, dominated by cholinergic (acetylcholine) and nitrergic (nitric oxide) neurons, respectively 52 , 53 . Recent work has suggested dopaminergic neurons play a role in peristalsis through regulation of nitrergic activity 53 .…”

“…Acetylcholine was chosen for prevalence and role in gut motility 50 , 52 . Dopamine was selected for its pathological link to PD 50 , 51 , 53 . Second, we aimed to model the pacemaking activity of local interstitial cells of Cajal (ICCs) using electrical stimulation with a square waveform (1200 mV for 1000 ms with 2000 ms break).…”

“…No work has yet described to our knowledge whether enteric neurons respond similarly, although clinical meta-analysis indicates constipation may precede PD symptoms by decades [7][8][9] , implicating ENS electrophysiological degeneration. Physiologically, the enteric nervous system (ENS) is a heterogenous population with at least 14 types of neurons and numerous neurotransmitters, including dopaminergic and cholinergic neurons, which conduct a wide range of functions, including gut motility [50][51][52][53] . Peristalsis is maintained through a complex excitation and inhibition pattern, dominated by cholinergic (acetylcholine) and nitrergic (nitric oxide) neurons, respectively 52,53 .…”

“…Physiologically, the enteric nervous system (ENS) is a heterogenous population with at least 14 types of neurons and numerous neurotransmitters, including dopaminergic and cholinergic neurons, which conduct a wide range of functions, including gut motility [50][51][52][53] . Peristalsis is maintained through a complex excitation and inhibition pattern, dominated by cholinergic (acetylcholine) and nitrergic (nitric oxide) neurons, respectively 52,53 . Recent work has suggested dopaminergic neurons play a role in peristalsis through regulation of nitrergic activity 53 .…”

Comparative transcriptomics reveals highly conserved regional programs between porcine and human colonic enteric nervous system

“…This is consistent with recent reports, implicating the role of TGF-beta in differentiation of nitrergic and catecholaminergic enteric neurons 43 , 44 . Recent study showed that the interactions of these two neuronal populations could stabilize asynchronous contractile activity and lead to the generation of colonic peristalsis in proximal colon 45 . However, our results suggested that the contribution of dopaminergic and nitrergic neurons to colonic peristalsis is much greater in p-dC than in p-pC.…”