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.