Evidence that stimulation of ghrelin receptors in the spinal cord initiates propulsive activity in the colon of the rat

Abstract

Previous studies have failed to reveal an effect of the gastrointestinal peptide hormone ghrelin on colonic motility. In the present work, ghrelin was applied into the lumbo-sacral spinal cord in the region of defecation control centres, and a synthetic ghrelin receptor agonist, CP464709, which crosses the blood-brain barrier, was applied intravenously or into the lumbo-sacral cord. Both ghrelin and CP464709 elicited propulsive contractions and emptying of the colon in anaesthetized rats. In conscious rats, subcutaneous CP464709 caused fecal expulsion. The sites of action and nerve pathways involved in the stimulation of the colon by ghrelin receptor activation were investigated in anaesthetized rats. Intrathecal application of CP464709 at L6-S1, but not application at ponto-medullary levels or to the thoracic spinal cord, elicited propulsive contractions. The stimulation evoked by intravenous CP464709 was prevented if the pelvic nerve outflows were severed, but not if the spinal cord was cut rostral to the defecation centre at L6-S3. The response was also blocked by hexamethonium. When ghrelin, applied intrathecally, was used to desensitize its receptors, the effect of intravenous CP464709 was blocked. CP464709 did not affect small intestine motility or the amplitudes of visceromotor reflexes caused by colorectal distension. It is concluded that activation of ghrelin receptors in the lumbo-sacral spinal cord triggers co-ordinated propulsive contractions that empty the colo-rectum. The pathways through which these responses are generated pass out of the spinal cord via the pelvic nerves and cause propulsive contractions through activation of enteric neurons.

Future Treatment of Constipation-associated Disorders: Role of Relamorelin and Other Ghrelin Receptor Agonists

“…This effect diminished at greater doses (> 20 mg/kg) suggesting a possible dose-dependent desensitization of receptors. 33,52 Consistently, rats injected with CP46470 intravenously demonstrated strong propulsive contractions in the colorectum, without changing the baseline motility of the colon. It is thus possible that the GRLN-R agonist activates the defecation center of the L6-S2 lumbo-sacral region of the spinal cord, stimulating autonomic nerve input and thus promoting colorectal motility, without direct effects on colonic smooth muscle cells.…”

“…It is thus possible that the GRLN-R agonist activates the defecation center of the L6-S2 lumbo-sacral region of the spinal cord, stimulating autonomic nerve input and thus promoting colorectal motility, without direct effects on colonic smooth muscle cells. 33,52 This effect was observed in conscious as well as in anesthetized rats, and was manifested by a substantial stimulation of defecation without affecting small intestinal motility.…”

“…33,52 When injected subcutaneously at a dose of 5 or 10 mg/kg, CP464709 caused a substantial stimulation of defecation in the first hour following administration, which represented fourfold increased defecation rates compared to vehicle-treated animals. This effect diminished at greater doses (> 20 mg/kg) suggesting a possible dose-dependent desensitization of receptors.…”

“…20,29,30 Numerous studies in rodents demonstrate an enhanced motor activity in the duodenum following administration of exogenous ghrelin in the fed or fasted state. [31][32][33] Moreover, the activation of GRLN-Rs by centrally penetrant GRLN-R agonists in the lumbosacral spinal cord initiates and enhances propulsive contractile activity in the distal colon. 33,34 Ghrelin induces contractile activity in the GI tract, but the short half-life and plasma instability of ghrelin impairs the usefulness.…”

“…[31][32][33] Moreover, the activation of GRLN-Rs by centrally penetrant GRLN-R agonists in the lumbosacral spinal cord initiates and enhances propulsive contractile activity in the distal colon. 33,34 Ghrelin induces contractile activity in the GI tract, but the short half-life and plasma instability of ghrelin impairs the usefulness. 35 Hence, small molecule-GRLN-R agonists with prolonged receptor activity currently represent an attractive therapeutic option for the management of lower GI tract motility disorders.…”