5‐HT1A Receptor Activation by Buspirone Facilitates Post‐Inflammatory Intestinal Hypersensitivity in a Rat Model

Abstract

Intestinal hypersensitivity is the most common symptom and cause of pain in patients with post-inflammatory irritable bowel syndrome (PI-IBS). Several lines of evidence suggest that central serotonin (5-HT) and its receptors significantly contribute to the phenomenon and therefore may be prospective therapeutic targets for relieving abdominal pain and discomfort in PI-IBS. We demonstrated previously that buspirone, a partial agonist of the 5-HT1A receptors, dose-dependently inhibited visceromotor reactions and medullary neuronal responses to noxious colorectal distension in healthy awake dogs and anesthetized rats, indicating the drug's antinociceptive properties in normal conditions. However, whether the 5-HT1A agonist can be beneficial for post-inflammatory intestinal hypersensitivity and hyperalgesia, which are thought to be associated with altered central 5-HT signaling, is still unknown. In the presented study, the effect of systemic buspirone (Sigma-Aldrich, USA) on intestinal hypersensitivity and its underlying neuronal mechanisms were evaluated in Wistar rats recovered from trinitrobenzene sulfonic acid (TNBS)-induced colitis. To assess gut sensitivity, the electromyography recordings of visceromotor reaction to colorectal distension (CRD) and extracellular microelectrode recordings of CRD-evoked caudal medulla neuronal responses were performed in conscious and urethane-anesthetized animals respectively. The results showed that in intestinal hypersensitive rats the visceromotor reaction and medullary neuronal responses to CRD in 40-60 days after TNBS treatment, despite the absence of obvious gut damage by this time, were increased compared with those in norm. Subcutaneous injection of buspirone (2 mg/kg), which exerted antinociceptive effect in healthy control group, further enhanced visceromotor reaction to CRD in post-colitis animals. In neurophysiological experiments on intestinal hypersensitivity rats, activation of the 5-HT1A receptors by intravenously administered buspirone (2 and 4 mg/kg) resulted in a dose-dependent increase of the CRD-evoked activity in the majority of the caudal medullary neurons, suggesting that the pro-algesic effect of the drug can at least partially be mediated by its excitatory action at the supraspinal level. These data demonstrate that the 5-HT1A agonist buspirone loses its antinociceptive properties in post-colitis conditions and thus may not be useful for reliving visceral hypersensitivity and hyperalgesia in PI-IBS.