Sacral nerve stimulation increases gastric accommodation in rats: a spinal afferent and vagal efferent pathway

Impaired gastric accommodation (GA) has been frequently reported in various gastrointestinal diseases. No standard treatment strategy is available for treating impaired GA. We explored the possible effect of sacral nerve stimulation (SNS) on GA and discovered a spinal afferent and vagal efferent mechanism in rats. Sprague-Dawley rats (450–500 g) with a chronically implanted gastric cannula and ECG electrodes were studied in a series of sessions to study: 1) the effects of SNS with different parameters on gastric tone, compliance, and accommodation using a barostat device; two sets of parameters were tested as follows: parameter 1) 5 Hz, 500 µs, 10 s on 90 s off; 90% motor threshold and parameter 2) same as parameter 1 but 25 Hz; 2) the involvement of spinal afferent pathway via detecting c-fos immunoreactive (IR) cells in the nucleus of the solitary tract (NTS) of the brain; 3) the involvement of vagal efferent activity via the spectral analysis of heart rate variability derived from the ECG; and 4) the nitrergic mechanism, Nω-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase (NOS) inhibitor, was given before SNS at 5 Hz. Compared with sham-SNS: 1) SNS at 5 Hz inhibited gastric tone and increased gastric compliance and GA. No difference was noted between the stimulation frequencies of 5 and 25 Hz. 2) SNS increased the expression of c-fos in the NTS. 3) SNS increased cardiac vagal efferent activity and decreased the sympathovagal ratio. 4) l-NAME blocked the relaxation effect of SNS. In conclusion, SNS with certain parameters relaxes gastric fundus and improves gastric accommodation mediated via a spinal afferent and vagal efferent pathway. NEW & NOTEWORTHY Currently, there is no adequate medical therapy for impaired gastric accommodation, since medications that relax the fundus often impair antral peristalsis and thus further delay gastric emptying that is commonly seen in patients with functional dyspepsia or gastroparesis. The advantage of the potential sacral nerve stimulation therapy is that it improves gastric accommodation by enhancing vagal activity, and the enhanced vagal activity would lead to enhanced antral peristalsis rather than inhibiting it.

Sex differences in GABAergic neurotransmission to rat DMV neurons

Functional gastrointestinal disorders, including delayed gastric emptying and decreased gastric motility, are more prevalent in women, suggesting a potential role for circulating gonadal hormones, including estrogen. Gastric motility is tuned by the vagal inputs arising from the dorsal motor nucleus of the vagus (DMV), which is itself controlled by tonic GABAergic inputs. Estrogen increases GABA functions in various central nervous system areas; however, the effect of the estrus cycle in modulating GABAergic inputs onto DMV neurons, hence vagal control of gastric motility, has not been investigated. The aim of the present study was to test the hypothesis that GABAergic tone to DMV neurons, hence the vagal output to the stomach, varies according to sex and the estrus cycle. Experiments were performed on age-matched Sprague-Dawley male and virgin female rats; females were subdivided according to the high-estrogen (HE) or low-estrogen (LE) period of their cycle. Whole-cell patch-clamp recordings were made from gastric-projecting DMV neurons, and the response to perfusion with the GABAA receptor antagonist bicuculline was examined. The response of corpus and antrum tone and motility to bicuculline microinjected in the dorsal vagal complex, recorded via strain gauges sewn to the anterior gastric surface, was also assessed. Bicuculline increased the firing rate of DMV neurons, as well as gastric tone and motility, to a larger extent in HE compared with LE or male rats, suggesting a higher GABAergic tone in HE female rats. Taken together, the data support the hypothesis that GABAergic tone to DMV neurons varies according to sex and estrus cycle. NEW & NOTEWORTHY GABAergic neurotransmission to the dorsal motor nucleus of the vagus (DMV) plays a pivotal role in the modulation of gastric tone and motility. Gastric motility is reduced in women and may contribute to the higher incidence of functional gastrointestinal disorders. In the present study, we report that GABAergic tone to rat DMV neurons, hence vagal output to the stomach, varies according to sex and estrus cycle, and the GABAergic tone is increased during the high-estrogen period of the estrus cycle.

Altered gastric tone and motility response to brain-stem dopamine in a rat model of parkinsonism

The majority of patients with Parkinson’s disease (PD) experience gastrointestinal dysfunction. Recently, we described a nigro-vagal pathway that uses dopaminergic (DA) inputs to the dorsal motor nucleus of the vagus (DMV) and A2 area neurons to modulate gastric motility and tone. This pathway is disrupted in a rodent model of PD. The aim of the present study was to test the hypothesis that brain-stem DA modulation of gastric tone and motility is altered in a rodent model of PD. Male Sprague-Dawley rats received three weekly intraperitoneal injections of paraquat (10 mg/kg) or saline (control). In naive conditions, microinjection of DA into the DMV induced a gastroinhibitory response in 100% of animals. In 19 of 28 PQ-treated animals, however, microinjection of DA into the DVC induced a biphasic response, with an initial increase in gastric tone and motility followed by a profound gastroinhibition. The excitatory response to DA microinjection was attenuated by a combination of DA type 1 (DA1)- and DA2-like receptor antagonists. Conversely, the inhibitory response was reduced by the DA2-like receptor antagonist only. Pretreatment with the α2-adrenoceptor antagonist yohimbine did not modulate the response to DA, thus excluding involvement of the A2 area. At the end of the experiments, induction of the Parkinson phenotype was confirmed by the presence of α-synuclein immunoreactivity in the DMV and substantia nigra pars compacta. These data suggest a maladaptive neural plasticity in brain-stem vagal circuits regulating gastric motility in PQ-treated rats that may be responsible for the gastric dysfunction observed in PD models. NEW & NOTEWORTHY After paraquat treatment and induction of Parkinson’s disease, brain-stem dopamine (DA) application induces a biphasic gastric response in the majority of rats, with an initial increase in tone and motility followed by gastroinhibition. The initial increase in gastric tone and motility is mediated via a combined activation of DA type 1 (DA1)- and DA2-like receptors. The inhibitory effects of DA are mediated by DA2-like receptors and are not affected by blockade of adrenergic inputs mediated by α2-adrenoceptors.

Vagally mediated gastric effects of brain stem α2-adrenoceptor activation in stressed rats

Chronic stress exerts vagally dependent effects to disrupt gastric motility; previous studies have shown that, among other nuclei, A2 neurons are involved in mediating these effects. Several studies have also shown robust in vitro and in vivo effects of α2-adrenoceptor agonists on vagal motoneurons. We have demonstrated previously that brainstem vagal neurocircuits undergo remodeling following acute stress; however, the effects following brief periods of chronic stress have not been investigated. Our aim, therefore, was to test the hypothesis that different types of chronic stress influence gastric tone and motility by inducing plasticity in the response of vagal neurocircuits to α2-adrenoreceptor agonists. In rats that underwent 5 days of either homotypic or heterotypic stress loading, we applied the α2-adrenoceptor agonist, UK14304, either by in vitro brainstem perfusion to examine its ability to modulate GABAergic synaptic inputs to vagal motoneurons or in vivo brainstem microinjection to observe actions to modulate antral tone and motility. In neurons from naïve rats, GABAergic currents were unresponsive to exogenous application of UK14304. In contrast, GABAergic currents were inhibited by UK14304 in all neurons from homotypic and, in a subpopulation of neurons, heterotypic stressed rats. In control rats, UK14304 microinjection inhibited gastric tone and motility via withdrawal of vagal cholinergic tone; in heterotypic stressed rats, the larger inhibition of antrum tone was due to a concomitant activation of peripheral nonadrenergic, noncholinergic pathways. These data suggest that stress induces plasticity in brainstem vagal neurocircuits, leading to an upregulation of α2-mediated responses. NEW & NOTEWORTHY Catecholaminergic neurons of the A2 area play a relevant role in stress-related dysfunction of the gastric antrum. Brief periods of chronic stress load induce plastic changes in the actions of adrenoceptors on vagal brainstem neurocircuits.

Apelin-13 inhibits gastric motility through vagal cholinergic pathway in rats

The expression of apelin and its receptors (APJ) in central autonomic networks suggests that apelin may regulate gastrointestinal motor functions. In rodents, central administration of apelin-13 has been shown to inhibit gastric emptying; however, the mechanisms involved remain to be determined. Using male adult Sprague-Dawley rats, the aims of the present study were 1) to determine the expression of APJ receptor in the dorsal vagal complex (DVC), 2) to assess the effects of central application of apelin-13 into the DVC on gastric tone and motility, and 3) to investigate the neuronal pathways responsible for apelin-induced alterations. APJ receptor immunoreactivity was detected in gastric-projecting and choline acetyltransferase-positive neurons of the DVC. Microinjection of apelin-13 into the DVC significantly decreased gastric tone and motility in both corpus and antrum. The apelin-induced reduction in gastric tone and motility was prevented by surgical vagotomy or fourth ventricular application of the APJ receptor antagonist, [Ala13]apelin-13 (F13A). Systemic administration of the muscarinic receptor antagonist atropine, but not the nitric oxide synthase inhibitor nitro-l-arginine methyl ester (l-NAME), abolished the apelin-induced inhibitory responses. The present results indicate a central modulatory role of apelin in the vagal neurocircuitry that controls gastric motor functions via withdrawal of the tonically active cholinergic pathway. NEW & NOTEWORTHY This is the first study investigating the effects induced by brain stem application of apelin-13 while monitoring gastric tone and motility in rats. We have found that gastric-projecting neurons of the dorsal vagal complex express apelin receptors (APJ), which mediate the inhibitory actions of apelin-13. The inhibitory effects of apelin were abolished by systemic preadministration of atropine, but not nitro-l-arginine methyl ester (l-NAME). Apelin seems to modulate gastric motility via withdrawal of the tonically active vagal cholinergic pathway.

Vagally mediated effects of brain stem dopamine on gastric tone and phasic contractions of the rat

Dopamine (DA)-containing fibers and neurons are embedded within the brain stem dorsal vagal complex (DVC); we have shown previously that DA modulates the membrane properties of neurons of the dorsal motor nucleus of the vagus (DMV) via DA1 and DA2 receptors. The vagally dependent modulation of gastric tone and phasic contractions, i.e., motility, by DA, however, has not been characterized. With the use of microinjections of DA in the DVC while recording gastric tone and motility, the aims of the present study were 1) assess the gastric effects of brain stem DA application, 2) identify the DA receptor subtype, and, 3) identify the postganglionic pathway(s) activated. Dopamine microinjection in the DVC decreased gastric tone and motility in both corpus and antrum in 29 of 34 rats, and the effects were abolished by ipsilateral vagotomy and fourth ventricular treatment with the selective DA2 receptor antagonist L741,626 but not by application of the selective DA1 receptor antagonist SCH 23390. Systemic administration of the cholinergic antagonist atropine attenuated the inhibition of corpus and antrum tone in response to DA microinjection in the DVC. Conversely, systemic administration of the nitric oxide synthase inhibitor nitro-l-arginine methyl ester did not alter the DA-induced decrease in gastric tone and motility. Our data provide evidence of a dopaminergic modulation of a brain stem vagal neurocircuit that controls gastric tone and motility. NEW & NOTEWORTHY Dopamine administration in the brain stem decreases gastric tone and phasic contractions. The gastric effects of dopamine are mediated via dopamine 2 receptors on neurons of the dorsal motor nucleus of the vagus. The inhibitory effects of dopamine are mediated via inhibition of the postganglionic cholinergic pathway.