Cannabinoids and novel opioids inhibit visceral nociception in a model of inflammatory bowel disease

Abstract

Background: Over 70% of inflammatory bowel disease (IBD) patients experience daily pain. Conventional opioids are often needed to manage severe pain but cause serious side effects. Alternative strategies are needed and cannabinoid-use has increased with its legalization. Additionally, a novel pH sensitive opioid, NFEPP, has been developed to be selectively active in acidified microenvironments (e.g. site of inflammation) and may have utility in IBD. However, it is unclear whether these compounds can inhibit visceral pain during colitis. I hypothesize that cannabinoids and NFEPP will inhibit pain during colitis without side effects. Methods: Visceral nociception was evaluated by studying visceromotor responses to colorectal distention, afferent nerve mechanosensitivity and dorsal root ganglia neuronal excitability in patch clamp studies of healthy mice and mice with acute dextran sulfate sodium colitis. Mass spectrometry analysis quantified endocannabinoid (2-AG, AEA) levels. Side effects of cannabinoids and opioids were measured using oxygen saturation, heart rate, locomotion and fecal pelleting assays. Human colonic afferent nerve recordings were also performed. Results: Cannabinoid 1 receptor (CB1R), but not CB2R, agonists inhibited nociception in healthy mice, measured by VMR, afferent nerve mechanosensitivity and DRG neuronal excitability. A combination of sub-analgesic doses of CB1R and MOR agonists synergistically inhibited pain without side effects or tolerance in healthy mice and was mediated, in part, by nitric oxide. During colitis, CB2R agonists inhibited visceral nociception, but CB1R agonists were less potent compared to healthy mice. 2-AG, but not AEA, increased in the colon during colitis. CB1R agonist potency returned after a CB1R antagonist was administered during development of colitis. Both CB1R and CB2R agonists synergistically interact with MOR agonists to inhibit visceral nociception in colitis. NFEPP inhibits nociception during colitis without adverse effects and had no effect in healthy mice, suggesting it is only active in an inflamed acidified microenvironment. CB1R agonists and NFEPP inhibit human colonic afferent nerve mechanosensitivity. Conclusion: Cannabinoids, alone or synergistically with opioids, inhibited visceral nociception in healthy and colitis mice, without adverse side effects or tolerance. NFEPP selectively inhibits nociception in the acidified microenvironment of colitis without side effects. These data demonstrate promising strategies for treatment of IBD-induced pain.