title: Group II mGluRs suppress hyperexcitability in mouse and human nociceptors.
abstract: We introduce a strategy for preclinical research wherein promising targets for analgesia are tested in rodent and subsequently validated in human sensory neurons. We evaluate group II metabotropic glutamate receptors, the activation of which is efficacious in rodent models of pain. Immunohistochemical analysis showed positive immunoreactivity for mGlu2 in rodent dorsal root ganglia (DRG), peripheral fibers in skin, and central labeling in the spinal dorsal horn. We also found mGlu2-positive immunoreactivity in human neonatal and adult DRG. RNA-seq analysis of mouse and human DRG revealed a comparative expression profile between species for group II mGluRs and for opioid receptors. In rodent sensory neurons under basal conditions, activation of group II mGluRs with a selective group II agonist produced no changes to membrane excitability. However, membrane hyperexcitability in sensory neurons exposed to the inflammatory mediator prostaglandin E2 (PGE2) was prevented by (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC). In human sensory neurons from donors without a history of chronic pain, we show that PGE2 produced hyperexcitability that was similarly blocked by group II mGluR activation. These results reveal a mechanism for peripheral analgesia likely shared by mice and humans and demonstrate a translational research strategy to improve preclinical validation of novel analgesics using cultured human sensory neurons.
authors.affiliation: Department of Anesthesiology, Pain Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.|S. Davidson is now with Pain Research Center, Department of Anesthesiology, University of Cincinnati, College of Medicine, Cincinnati, OH, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Davidson
authors.affiliation: Department of Anesthesiology, Pain Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
authors.forename: Judith P
authors.initials: JP
authors.lastname: Golden
authors.affiliation: Department of Anesthesiology, Pain Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Copits
authors.affiliation: School of Sciences, University of Texas at Dallas School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA.
authors.forename: Pradipta R
authors.initials: PR
authors.lastname: Ray
authors.affiliation: Department of Anesthesiology, Pain Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
authors.forename: Sherri K
authors.initials: SK
authors.lastname: Vogt
authors.affiliation: Department of Anesthesiology, Pain Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
authors.forename: Manouela V
authors.initials: MV
authors.lastname: Valtcheva
authors.affiliation: Department of Neuropathology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: AnaBios Corporation, San Diego, CA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ghetti
authors.affiliation: School of Sciences, University of Texas at Dallas School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
authors.affiliation: Department of Anesthesiology, Pain Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gereau
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: D018690:Excitatory Amino Acid Agonists; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; D014404:Tubulin; C108822:metabotropic glutamate receptor 2; D015740:Calcitonin Gene-Related Peptide; D015232:Dinoprostone