A Novel Charged Sodium-Channel Blocker, Ntx-1175, Is Effective In Reducing Acute Visceral Hypersensitivity In Vivo

Abstract

<b>Abstract ID 21618</b> <b>Poster Board 453</b> <b>Background:</b> Chronic abdominal pain is a hallmark feature of irritable bowel syndrome (IBS), a disorder of gut-brain communication with no observable tissue damage. In patients with IBS, chronic abdominal pain is the result of visceral hypersensitivity due to visceral afferent nerve sensitization. We have previously demonstrated that an enema of dilute (0.6% v/v) acetic acid (AA) provides a model of acute colonic hypersensitivity to distension. Sensory nerves can be selectively inhibited by charged sodium channel blockers (CSCBs) such as NTX-1175 through gaining access to nociceptors through large pore channels (e.g., Transient Receptor Potential (TRP)V1, TRPA1) that are open due to ongoing pain and inflammation. The goal of the current study was to evaluate the effect of the novel CSCB NTX-1175 in a rodent model of colonic hypersensitivity in male rats. <b>Methods:</b> Thirty adult male Sprague Dawley rats were randomly assigned to saline enema/vehicle intracolonic (i.c.), AA enema/vehicle enema, or AA enema/NTX-1175 (i.c.) at 10, 25, or 50 mg/kg. For each rat, the saline or AA enema was administered before the drug/vehicle dosing. Sixty-minutes after the dosing, colonic sensitivity was quantified as the number of abdominal contractions, to graded pressures (0, 20, 40, 60 mmHg) of isobaric colorectal distension (CRD). At euthanasia, plasma and colonic tissue were collected for pK analysis. Data was presented as mean ± standard error of the mean. Two-factor repeated measure ANOVA with Bonferroni post-hoc test or unpaired t-tests were used for analysis, n=6/group. <b>Results:</b> We first verified that the AA model induced colonic hypersensitivity as measured by increased abdominal contractions compared to the saline enema controls (40 mmHg: AA=24.8±1.2 vs. saline=11.7±1.2, p&lt;0.01; 60 mmHg: AA=30.7±2.4 vs. saline=15.7±1.3, p&lt;0.01). Intracolonic administration of NTX-1175 provided a dose-responsive effect with significant attenuation of AA-induced colonic hypersensitivity at the highest dose tested (40 mmHg: 10 mg/kg=22.2±0.9, p&gt;0.05; 25 mg/kg=19.7±2.3, p&gt;0.05; 50 mg/kg=13.5±1.3, p&lt;0.01; 60 mmHg: 10 mg/kg=26.8±1.3, p&gt;0.05; 25 mg/kg=24.3±2.5, p&gt;0.05; 50 mg/kg=19.0±1.4, p&lt;0.05). At 50 mg/kg i.c., there was significantly more NTX-1175 in the colon than the plasma (83,700±33,000 ng/g tissue vs. 11.5±1.2 ng/ml plasma, p&lt;0.01). <b>Summary and Conclusions:</b> In a rat model colonic hypersensitivity, treatment with the novel CSCB NTX-1175 delivered directly into to the colon normalized colonic sensitivity in a dose-dependent manner. This is the first report of using a CSCB therapy to attenuate visceral pain, providing proof of concept rationale for the treatment of disorders such as IBS. Funding provided by Nocion Therapeutics