Antinociceptive Effect of Ghrelin in a Rat Model of Irritable Bowel Syndrome Involves TRPV1/Opioid Systems

Abstract

Background/Aims: Irritable bowel syndrome (IBS), defined as recurrent abdominal pain and changes in bowel habits, seriously affects quality of life and ability to work. Ghrelin is a brain-gut hormone, which has been reported to show antinociceptive effects in peripheral pain. We investigated the effect of ghrelin on visceral hypersensitivity and pain in a rat model of IBS. Methods: Maternal deprivation (MD) was used to provide a stress-induced model of IBS in Wistar rats. Colorectal distension (CRD) was used to detect visceral sensitivity, which was evaluated by abdominal withdrawal reflex (AWR) scores. Rats that were confirmed to have visceral hypersensitivity after MD were injected with ghrelin (10 µg/kg) subcutaneously twice a week from weeks 7 to 8. [D-Lys3]-GHRP-6 (100 nmol/L) and naloxone (100 nmol/L) were administered subcutaneously to block growth hormone secretagogue receptor 1α (GHS-R1α) and opioid receptors, respectively. Expression of transient receptor potential vanilloid type 1 (TRPV1) and µ and κ opioid receptors (MOR and KOR) in colon, dorsal root ganglion (DRG) and cerebral cortex tissues were detected by western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical analyses and immunofluorescence. Results: Ghrelin treatment increased expression of opioid receptors and inhibited expression of TRPV1 in colon, dorsal root ganglion (DRG) and cerebral cortex. The antinociceptive effect of ghrelin in the rat model of IBS was partly blocked by both the ghrelin antagonist [D-Lys3]-GHRP-6 and the opioid receptor antagonist naloxone. Conclusion: The results indicate that ghrelin exerted an antinociceptive effect, which was mediated via TRPV1/opioid systems, in IBS-induced visceral hypersensitivity. Ghrelin might potentially be used as a new treatment for IBS.

Physiological Effect of Ghrelin on Body Systems

“…Ghrelin has also an effect on the sensory function of the nervous system. It has been reported to have analgesic effects on peripheral pain in the rat model which was mediated via transient receptor potential vanilloid type I opioid systems [90]. A recent study done on mice revealed that injection of ghrelin initially activated the GHSR1a, which in turn increased the release of endogenous proenkephalin for activation of the δ-opioid receptor to produce antinociception [91].…”

Ghrelin inhibits autonomic response to gastric distension in rats by acting on vagal pathway

“…The antinociceptive or antihypersensitive action of ghrelin was previously reported in somatic pain [10][11][12][13] and colonic distension models 14,16 . In the stomach, the role of ghrelin on gastroesophageal vagal afferents excitability has already been investigated on mouse ex vivo preparation by decreasing the response of tension receptors 17 .…”

Efficacy and Safety of Ghrelin Agonists in Patients with Diabetic Gastroparesis: A Systematic Review and Meta-Analysis

“… 6 The ghrelin infusion reduced gastric accommodation in the clinical trial for healthy volunteers and at least one preclinical study suggests that ghrelin has antinociceptive effects, which counter visceral hypersensitivity. 31 , 32 Indeed, ghrelin agonists act to reduce GET, visceral hypersensitivity and gastric accommodation, thereby improving nausea, vomiting, early satiety, and abdominal pain. On the other hand, bloating may be a heterogeneous condition involving multiple pathophysiologic factors.…”