Stimulation of dopamine D2‐like receptors in the lumbosacral defaecation centre causes propulsive colorectal contractions in rats

Abstract

Key pointsr The pathophysiological roles of the CNS in bowel dysfunction in patients with irritable bowel syndrome and Parkinson's disease remain obscure.r In the present study, we demonstrate that dopamine in the lumbosacral defaecation centre causes strong propulsive motility of the colorectum.r The effect of dopamine is a result of activation of sacral parasympathetic preganglionic neurons via D2-like dopamine receptors.r Considering that dopamine is a neurotransmitter of descending pain inhibitory pathways, our results highlight the novel concept that descending pain inhibitory pathways control not only pain, but also the defaecation reflex.r In addition, severe constipation in patients with Parkinson's disease can be explained by reduced parasympathetic outflow as a result of a loss of the effect of dopaminergic neurons. AbstractWe have recently demonstrated that intrathecally injected noradrenaline caused propulsive contractions of the colorectum. We hypothesized that descending pain inhibitory pathways control not only pain, but also the defaecation reflex. Because dopamine is one of the major neurotransmitters of descending pain inhibitory pathways in the spinal cord, we examined the effects of the intrathecal application of dopamine to the spinal defaecation centre on colorectal motility. Colorectal intraluminal pressure and expelled volume were recorded in vivo in anaesthetized rats. Slice patch clamp and immunohistochemistry were used to confirm the existence of dopamine-sensitive neurons in the sacral parasympathetic nuclei. Intrathecal application of dopamine into the L6-S1 spinal cord, where the lumbosacral defaecation centre is located, caused propulsive contractions of the colorectum. Inactivation of spinal neurons using TTX blocked the effect of dopamine. Although thoracic spinal transection had no effect on the enhancement of colorectal motility by intrathecal dopamine, the severing of the pelvic nerves abolished the enhanced motility. Pharmacological experiments revealed that the effect of dopamine is mediated primarily by D2-like dopamine receptors. Neurons labelled with retrograde dye injected at the colorectum showed an inward current in response to dopamine in slice patch clamp recordings. Furthermore, immunohistochemical analysis revealed that neurons immunoreactive to choline acetyltransferase express D2-like dopamine receptors. Taken together, our findings demonstrate that dopamine activates sacral parasympathetic preganglionic neurons via D2-like dopamine receptors and causes propulsive motility of the colorectum in rats. The present study supports the hypothesis that descending pain inhibitory pathways regulate defaecation reflexes.

<b>Noradrenergic effects in rat sacral autonomic nucleus using in vitro slice patch-clamp r</b><b>ecordings </b>

“…The reverse potential of K + in this experiment was around −90 mV, which the pontine micturition center, and administration of NA initiates the micturition reflex in some bladder conditions (28). Also, α1 receptor-mediated facilitations of colonic mortalities in the spinal cord were reported in defecation systems (22,23). Our findings showing excitation through α1 receptor of labeled-PGNs and enhancement of sEPSC may explain the mechanisms of those reports.…”

“…Recordings were obtained from 96 SPN neurons labeled by retrograde axonal transport of a fluorescent dye and established under differential interference contrast optics as described previously (19,23). After obtaining the whole-cell recording (Fig.…”

“…The involvement of NAergic modulations of SPN neural activities has been widely discussed and the effect is not so simple (5,7,13,23). Early experiments (25,34) showed the importance of brainstem-spinal NAergic modulation of micturition reflex.…”

“…Also as described previously (23,25), we recorded DiI-labeled SPN neurons from rats that had been injected with the retrograde tracer fast DiI (1,1'-dilinoleyl-3,3,3',3'-tetramethylidocarbocyanine, 4-chlorobenzensulfonate+; Molecular Probes, Eugene, OR, USA; 10 μL, 20 μg/μL dissolved in DMSO) into the peritoneal cavity at 9-11 days after birth. Animals were used 3-10 days after the injection.…”

“…Patch-clamp recordings from retrogradely labeled PGNs in the SPN in vitro slices were performed. We used Fast-DiI labeling from the pelvic viscera and fluorescence microscopy to identify the PGNs within the SPN (18,23). In this study, NA induced both inward and outward currents through α1 and α2 receptors.…”