title: Brainstem facilitations and descending serotonergic controls contribute to visceral nociception but not pregabalin analgesia in rats.
abstract: 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-HT(3) receptor antagonist ondansetron, we demonstrate pro-nociceptive serotonergic modulation of visceral nociception and a facilitatory drive from RVM MOR cells. The α(2)δ 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.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, WC1E 6BT London, UK. shafaq.sikandar@ucl.ac.uk
authors.forename: Shafaq
authors.initials: S
authors.lastname: Sikandar
authors.forename: Kirsty
authors.initials: K
authors.lastname: Bannister
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Dickenson
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D004525:Efferent Pathways / Q000187:drug effects / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D059225:Nociception / Q000187:drug effects*; D000069583:Pregabalin; D051381:Rats; D017207:Rats, Sprague-Dawley; D059326:Serotonergic Neurons / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D059265:Visceral Pain / Q000378:metabolism* / Q000517:prevention & control*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D012701:Serotonin; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid