Beta 3-Adrenoceptor Agonism Ameliorates Early Life Stress-Induced Visceral Hypersensitivity in Male Rats.

Visceral hypersensitivity, a hallmark of disorders of the gut-brain axis, is associated with exposure to early life stress (ELS). Activation of neuronal β3-adrenoceptors (AR) has been shown to alter central and peripheral levels of tryptophan and reduce visceral hypersensitivity. In this study, we aimed to determine the potential of a β3-AR agonist in reducing ELS-induced visceral hypersensitivity and possible underlying mechanisms. Here, ELS was induced using the maternal separation (MS) model, where Sprague Dawley rat pups were separated from their mother in early life (postnatal day 2-12). Visceral hypersensitivity was confirmed in adult offspring using colorectal distension (CRD). CL-316243, a β3-AR agonist, was administered to determine anti-nociceptive effects to CRD. Distension-induced enteric neuronal activation as well as colonic secretomotor function were assessed. Tryptophan metabolism was determined both centrally and peripherally. For the first time, we show that CL-316243 significantly ameliorates MS-induced visceral hypersensitivity. Furthermore, MS altered plasma tryptophan metabolism and colonic adrenergic tone while CL-316243 reduced both central and peripheral levels of tryptophan and affected secretomotor activity in the presence of tetrodotoxin. This study supports a beneficial role of CL-316243 in reducing ELS-induced visceral hypersensitivity and suggests that targeting the β3-AR can significantly influence gut-brain axis activity through modulation of enteric neuronal activation, tryptophan metabolism, and colonic secretomotor activity which may synergistically contribute to offsetting the effects of ELS.