5-Hydroxytryptamine 1A (5-HT(1A)) receptors have been suggested as a target for the treatment of
irritable bowel syndrome (IBS). A recent clinical trial investigating the efficacy of the selective 5-HT(1A) antagonist AZD7371 [3(R)-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-
benzopyran-5-carboxamide (R,R)-
tartrate monohydrate] showed no symptomatic improvement in IBS patients. We characterized the mechanisms mediating potential
analgesic effects of AZD7371 in a model of colorectal distension (CRD)-induced
visceral pain in rats to understand its mechanism of action and the lack of clinical efficacy. Visceromotor and cardiovascular responses (telemetry) were assessed in conscious rats during noxious CRD (80 mm Hg). Effects of AZD7371 (3-300 nmol/kg i.v.; 1-30 micromol/kg p.o.) and a reference 5-HT(1A) antagonist,
WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide
maleate salt; 3-300 nmol/kg i.v.), were assessed. Effects of intracerebroventricular AZD7371 were also evaluated. Intravenous AZD7371 or
WAY-100635 and oral AZD7371 dose-dependently inhibited visceromotor responses to CRD (ED(50), 203, 231, and 14 micromol/kg, respectively). In telemetrized rats, oral AZD7371 inhibited visceromotor responses to CRD without affecting the concomitant hypertensive and tachycardic responses. Intracerebroventricular AZD7371 did not affect visceromotor responses, whereas it inhibited micturition. None of the doses tested induced visible gross side effects. AZD7371, likely acting at a spinal site, inhibited the visceromotor but not the cardiovascular responses to
visceral pain in the CRD model in rats. Although agents effective on multiple
pain-related readouts in the CRD model (e.g.,
pregabalin or
clonidine) alleviate IBS symptoms, AZD7371, which is effective on only one
pain-related pseudoaffective readout, does not. Data from preclinical CRD models of
visceral pain need to be interpreted cautiously as it relates to their clinical translational value.