Activation of the endogenous nociceptin system by selective nociceptin receptor agonist SCH 221510 produces antitransit and antinociceptive effect: a novel strategy for treatment of diarrhea‐predominant IBS

Abstract

Collectively, mouse and human data suggest that the endogenous nociceptin system is involved in IBS-D and may become a target for anti-IBS-D treatments using potent and selective synthetic NOP agonists.

Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility

“…Among recent therapeutic applications explored in animal models with compound 12 as a NOP agonist tool compound, are reports that NOP agonists show significant antinociceptive and anti-inflammatory efficacy in mouse models of intestinal disorders such as inflammatory bowel disease (IBD) 113 and diarrhea-predominant IBD. 114 Interestingly, only the i.p.…”

Opioidergic effects on enteric and sensory nerves in the lower GI tract: basic mechanisms and clinical implications

“…Much less is known regarding the functional effects that NOR has on enteric nerve function in the GI tract, reflecting the relatively recent discovery of this system. NOR agonists inhibit GI motility in vivo in a similar way to the classical opioid receptor family members, and the majority of myenteric neurons in the colon and ileum express NOR, particularly those that express NO synthase and ChAT (16,35,91,103,104,116) (Fig. 1).…”

“…NOR has been identified on neurons not only with Dogiel type I morphology but, in contrast to classical opioid receptor family members, also those with Dogiel type II morphology, indicating NOR potentially regulates a wider range of physiological processes than classical opioids (69,116). NOR agonists have no effect on spontaneous contractions or on basal contractility of ileal or colonic smooth muscle, reflecting their lack of expression in smooth muscle, but they do inhibit electrical field-stimulated contractions, indicating a neurally mediated effect (35,82,116) (Table 1). More detailed investigations indicate that this effect is due to NOR expression on cholinergic excitatory motoneurons, which have also been shown to express nociceptin (80,103,104,116).…”

“…Interestingly, nearly one-third of neurons that express nociceptin also express enkephalin, and electrically stimulated secretion of enkephalin from myenteric Review G504 OPIOIDS AND GI NERVES neurons is modulated by nociceptin (46), suggesting opioidergic pathways may regulate each other. Targeting the NOR pathway may be beneficial in diarrhea, as selective NOR agonism by nociceptin, UFP-113, or SCH-221501 inhibited GI motility in both the castor oil and neostigmine models of diarrhea and hypermotility (16,35). These effects were most likely mediated by peripheral mechanisms, as CNS concentrations remained low during the testing period (35).…”

“…Targeting the NOR pathway may be beneficial in diarrhea, as selective NOR agonism by nociceptin, UFP-113, or SCH-221501 inhibited GI motility in both the castor oil and neostigmine models of diarrhea and hypermotility (16,35). These effects were most likely mediated by peripheral mechanisms, as CNS concentrations remained low during the testing period (35).…”