Agonist that activates the µ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects

Abstract

ObjectiveThe effectiveness of µ-opioid receptor (MOPr) agonists for treatment of visceral pain is compromised by constipation, respiratory depression, sedation and addiction. We investigated whether a fentanyl analogue, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), which preferentially activates MOPr in acidified diseased tissues, would inhibit pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues.DesignAntinociceptive actions of NFEPP and fentanyl were compared in control mice and mice with dextran sodium sulfate colitis by measuring visceromotor responses to colorectal distension. Patch clamp and extracellular recordings were used to assess nociceptor activation. Defecation, respiration and locomotion were assessed. Colonic migrating motor complexes were assessed by spatiotemporal mapping of isolated tissue. NFEPP-induced MOPr signalling and trafficking were studied in human embryonic kidney 293 cells.ResultsNFEPP inhibited visceromotor responses to colorectal distension in mice with colitis but not in control mice, consistent with acidification of the inflamed colon. Fentanyl inhibited responses in both groups. NFEPP inhibited the excitability of dorsal root ganglion neurons and suppressed mechanical sensitivity of colonic afferent fibres in acidified but not physiological conditions. Whereas fentanyl decreased defecation and caused respiratory depression and hyperactivity in mice with colitis, NFEPP was devoid of these effects. NFEPP did not affect colonic migrating motor complexes at physiological pH. NFEPP preferentially activated MOPr in acidified extracellular conditions to inhibit cAMP formation, recruit β-arrestins and evoke MOPr endocytosis.ConclusionIn a preclinical IBD model, NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce antinociception without causing respiratory depression, constipation and hyperactivity.

New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders

“…12 An alternative smart approach to achieve analgesia with m-OR activation and low risk of respiratory depression is provided by NFEPP, a fluorinated fentanyl molecule 13 that is activated selectively in acidic environments, such as in sites of inflammation. In mice with 2.5% dextran sodium sulphate-induced colitis, 14 NFEPP was associated with inhibition of visceromotor responses to colorectal distension, without decreased defecation or respiratory depression. In contrast to the m-OR-biased ligands, which activate the G protein-coupled receptor (GPCR) pathway without activating b-arrestin, NFEPP (in addition to activation of the opioid GPCR signaling pathway) actually recruits barrestins and evokes m-OR endocytosis leading to activation of m-ORs in endosomes.…”

“…Studies in humans with these novel m-OR ligands are eagerly awaited. In addition, it is not yet proven that the degree of inflammation in functional or motility disorders results in sufficient tissue acidification to activate the fluorinated fentanyl; preclinical models 14 show that an average tissue pH acidification by 0.33 units is sufficient to activate NFEPP.…”

Brain Renin–Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer’s Disease

“…To tackle this problem, Jimenez-Vargas and co-workers designed a nanoparticle system that takes advantage of the acidic pH present inside the lysosomes where the GPCRs are internalized. These nanoparticles have a ligand that inactivates the G protein signaling downstream of the GPCRs and is only released under the lysosome acidic conditions, avoiding the non-specific binding associated with GPCRs inhibitors and decreasing the effective dose in orders of magnitude [ 99 ].…”

Modelling altered signalling of G-protein coupled receptors in inflamed environment to advance drug design

“…Since the generation of pain can be effectively inhibited by blocking the electrical excitation of sensory neurons at the site of the injury (i.e. the origin of nociceptive stimulation), this gives rise to the hope that NFEPP might have less or even no adverse effects, which could already be corroborated in animal studies [2,4,5,6].…”