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Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

Dietary, microbial, and inflammatory factors modulate the gut-brain axis and influence physiological processes ranging from metabolism to cognition. The gut epithelium is a principal site for detecting such agents, but precisely how it communicates with neural elements is poorly understood. Serotonergic enterochromaffin (EC) cells are proposed to fulfill this role by acting as chemosensors, but understanding how these rare and unique cell types transduce chemosensory information to the nervous system has been hampered by their paucity and inaccessibility to single-cell measurements. Here, we circumvent this limitation by exploiting cultured intestinal organoids together with single-cell measurements to elucidate intrinsic biophysical, pharmacological, and genetic properties of EC cells. We show that EC cells express specific chemosensory receptors, are electrically excitable, and modulate serotonin-sensitive primary afferent nerve fibers via synaptic connections, enabling them to detect and transduce environmental, metabolic, and homeostatic information from the gut directly to the nervous system.

Olorinab—a highly selective, full agonist of the cannabinoid receptor 2—significantly reduces visceral hypersensitivity and colonic nociceptor firing in inflammatory bowel disease–like and irritable bowel syndrome–like rodent models., Abdominal pain is a key symptom of inflammatory bowel disease and irritable bowel syndrome, for which there are inadequate therapeutic options. We tested whether olorinab—a highly selective, full agonist of the cannabinoid receptor 2 (CB2)—reduced visceral hypersensitivity in models of colitis and chronic visceral hypersensitivity (CVH). In rodents, colitis was induced by intrarectal administration of nitrobenzene sulfonic acid derivatives. Control or colitis animals were administered vehicle or olorinab (3 or 30 mg/kg) twice daily by oral gavage for 5 days, starting 1 day before colitis induction. Chronic visceral hypersensitivity mice were administered olorinab (1, 3, 10, or 30 mg/kg) twice daily by oral gavage for 5 days, starting 24 days after colitis induction. Visceral mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMRs) to colorectal distension. Ex vivo afferent recordings determined colonic nociceptor firing evoked by mechanical stimuli. Colitis and CVH animals displayed significantly elevated VMRs to colorectal distension and colonic nociceptor hypersensitivity. Olorinab treatment significantly reduced VMRs to control levels in colitis and CVH animals. In addition, olorinab reduced nociceptor hypersensitivity in colitis and CVH states in a concentration- and CB2-dependent manner. By contrast, olorinab did not alter VMRs nor nociceptor responsiveness in control animals. Cannabinoid receptor 2 mRNA was detected in colonic tissue, particularly within epithelial cells, and dorsal root ganglia, with no significant differences between healthy, colitis, and CVH states. These results demonstrate that olorinab reduces visceral hypersensitivity through CB2 agonism in animal models, suggesting that olorinab may provide a novel therapy for inflammatory bowel disease– and irritable bowel syndrome–associated abdominal pain.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic urological condition characterised by urinary urgency, frequency and pelvic pain, that significantly impacts the quality of life for ∼5% of women. Bladder sensation is coordinated by primary afferent sensory neurons that innervate the bladder wall, translating bladder stretch into signals that travel to the brain via the spinal cord. Whilst the pathophysiology of IC/BPS remains unknown, an increase in the permeability of the bladder urothelium has been proposed as an initiating cause. Here we experimentally increased bladder permeability and tracked bladder afferent sensitivity for up to 28 days. We found that one day after increasing bladder epithelial permeability with in vivo bladder infusion of protamine sulfate, mechanosensitive bladder afferents exhibited significant hypersensitivity to bladder filling. This mechanical hypersensitivity was characterised by significantly increased peak afferent firing rates and a decrease in the activation threshold of individual afferents. Bladder afferent hypersensitivity occurred in the absence of inflammation and changes in bladder muscle compliance, indicating a direct sensitisation of peripheral afferent endings. Bladder afferent mechanosensitive responses to distension returned to control levels by day 7 post-protamine sulfate treatment and remained at control levels at 28-days post-treatment. Here we demonstrate, contrary to the prevailing hypothesis, that increased bladder permeability alone does not induce chronic bladder afferent sensitisation. Whilst experimentally induced changes in bladder permeability are able to induce transient bladder afferent hypersensitivity in the absence of inflammation, highly regulated homeostatic mechanisms exist to rapidly repair the urothelial barrier and normalise bladder afferent mechanosensitivity. Together, these data suggest that additional pathophysiology is required to induce chronic bladder dysfunction. Refereed/Peer-reviewed