Brainstem facilitations and descending serotonergic controls contribute to visceral nociception but not pregabalin analgesia in rats

Pro-nociceptive ON-cells in the rostral ventromedial medulla (RVM) facilitate nociceptive processing and contribute to descending serotonergic controls. We use RVM injections of neurotoxic dermorphin-saporin (Derm-SAP) in rats to evaluate the role of putative ON-cells, or μ-opioid receptor-expressing (MOR) neurones, in visceral pain processing. Our immunohistochemistry shows that intra-RVM Derm-SAP locally ablates a substantial proportion of MOR and serotonergic cells. Given the co-localization of these neuronal markers, some RVM ON-cells are serotonergic. We measure visceromotor responses in the colorectal distension (CRD) model in control and Derm-SAP rats, and using the 5-HT3 receptor antagonist ondansetron, we demonstrate pro-nociceptive serotonergic modulation of visceral nociception and a facilitatory drive from RVM MOR cells. The α2δ calcium channel ligand pregabalin produces state-dependent analgesia in neuropathy and osteoarthritis models relating to injury-specific interactions with serotonergic facilitations from RVM MOR cells. Although RVM MOR cells mediate noxious mechanical visceral input, we show that their presence is not a permissive factor for pregabalin analgesia in acute visceral pain.

► Descending 5-HT3 receptor-mediated controls are pro-nociceptive in visceral pain. ► Some μ-opioid receptor-expressing RVM cells, putative ON-cells, are serotonergic. ► Putative RVM ON-cells mediate basal visceral pain responses in the CRD model. ► Pregabalin inhibits evoked visceral pain in rats with ablated RVM ON-cells. ► State-dependent pregabalin analgesia in neuropathy does not apply to visceral pain.