title: Sensory neuron-specific receptor activation elicits central and peripheral nociceptive effects in rats.
abstract: The sensory neuron-specific G protein coupled receptors (SNSRs) have been described as a family of receptors whose expression in small diameter sensory neurons in the trigeminal and dorsal root ganglia suggests an implication in nociception. To date, the physiological function(s) of SNSRs remain unknown. Hence, the aim of the present study was to determine the effects of rat SNSR1 activation on nociception in rats. The pharmacological characterization of rat SNSR1 was initially performed in vitro to identify a specific ligand, which could be used subsequently in the rat for physiological testing. Among all ligands tested, gamma2-MSH was the most potent at activating rat SNSR1. Structure-activity relationship studies revealed that the active moiety recognized by rat SNSR1 was the C-terminal part of gamma2-MSH. The radiolabeled C-terminal part of gamma2-MSH, gamma2-MSH-6-12, bound with high affinity to membranes derived from rat skin and spinal cord, demonstrating the presence of receptor protein at both the proximal and distal terminals of dorsal root ganglia. To investigate the physiological role of SNSR, specific ligands to rat SNSR1 were tested in behavioral assays of pain sensitivity in rats. Selective rat SNSR1 agonists produced spontaneous pain behavior, enhanced heat and mechanical sensitivity when injected intradermally, and heat hypersensitivity when injected centrally, consistent with the localization of rat SNSR1 protein at central and peripheral sites. Together, these results clearly indicate that the SNSR1 plays a role in nociception and may provide novel therapeutic opportunities for analgesia.
authors.affiliation: AstraZeneca R & D Montréal, 7171 Frederick-Banting, Ville Saint-Laurent, Québec, Canada H4S 1Z9. eric.grazzini@astrazeneca.com
authors.forename: Eric
authors.initials: E
authors.lastname: Grazzini
authors.forename: Carole
authors.initials: C
authors.lastname: Puma
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Roy
authors.forename: Xiao Hong
authors.initials: XH
authors.lastname: Yu
authors.forename: Dajan
authors.initials: D
authors.lastname: O'Donnell
authors.forename: Ralf
authors.initials: R
authors.lastname: Schmidt
authors.forename: Sophie
authors.initials: S
authors.lastname: Dautrey
authors.forename: Julie
authors.initials: J
authors.lastname: Ducharme
authors.forename: Martin
authors.initials: M
authors.lastname: Perkins
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Panetta
authors.forename: Jennifer M A
authors.initials: JM
authors.lastname: Laird
authors.forename: Sultan
authors.initials: S
authors.lastname: Ahmad
authors.forename: Paola M C
authors.initials: PM
authors.lastname: Lembo
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D006801:Humans; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism*; D010146:Pain / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D009074:Melanocyte-Stimulating Hormones