Postcolitis Alterations in Dose-Dependent Effects of 5-HT1A Agonist Buspirone on Nociceptive Activity of the Raphe Magnus and Dorsal Raphe Neurons in Rats

The serotonergic raphe magnus (RMg) and dorsal raphe (DR) nuclei are crucial pain–regulating structures, which nociceptive activity is shown to be altered in gut pathology, but the underlying neuroplastic changes remain unclear. Considering the importance of 5-HT1A receptors in modulating both pain and raphe neuronal activity, in this study, we aimed to determine whether 5-HT1A-dependent visceral and somatic nociceptive processing within the RMg and DR is modified in postcolitis conditions. In anaesthetised male Wistar rats, healthy control and recovered from TNBS-induced colitis, the microelectrode recordings of RMg and DR neuron responses to noxious colorectal distension (CRD) or tail squeezing (TS) were performed prior and after intravenous administration of 5-HT1A agonist, buspirone. In postcolitis animals, 5-HT1A autoreceptor- and heteroreceptor-activating high doses of buspirone (2 and 4 mg/kg) lost normally occurring ability to facilitate CRD- and TS-evoked activation of RMg neurons, causing inhibition of the local nociceptive signalling similar to 5-HT1A autoreceptor-activating low doses (0.1 and 0.5 mg/kg). Conversely, the normally inherent property of buspirone at all doses to reduce visceral and somatic pain–related neuronal excitation in the DR was weakened after colitis. These phenomena were associated with a loss of normally occurring inhibitory effect of the compound's high doses on hemodynamic reactions to CRD and TS, revealing deficient antinociceptive action at a systemic level. The data suggest postcolitis changes in buspirone-dependent 5-HT1A autoreceptor- and heteroreceptor-mediated signalling, which can directly or indirectly lead to reduced RMg pain–related activity and increased DR nociceptive excitation, impairing their functioning in the visceral and somatic pain control.