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

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.