title: GINIP, a Gαi-interacting protein, functions as a key modulator of peripheral GABAB receptor-mediated analgesia.
abstract: One feature of neuropathic pain is a reduced GABAergic inhibitory function. Nociceptors have been suggested to play a key role in this process. However, the mechanisms behind nociceptor-mediated modulation of GABA signaling remain to be elucidated. Here we describe the identification of GINIP, a Gαi-interacting protein expressed in two distinct subsets of nonpeptidergic nociceptors. GINIP null mice develop a selective and prolonged mechanical hypersensitivity in models of inflammation and neuropathy. GINIP null mice show impaired responsiveness to GABAB, but not to delta or mu opioid receptor agonist-mediated analgesia specifically in the spared nerve injury (SNI) model. Consistently, GINIP-deficient dorsal root ganglia neurons had lower baclofen-evoked inhibition of high-voltage-activated calcium channels and a defective presynaptic inhibition of lamina IIi interneurons. These results further support the role of unmyelinated C fibers in injury-induced modulation of spinal GABAergic inhibition and identify GINIP as a key modulator of peripherally evoked GABAB-receptors signaling.
authors.affiliation: Aix-Marseille-Université, CNRS, Institut de Biologie du Développement de Marseille, UMR 7288, case 907, 13288 Marseille Cedex 09, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gaillard
authors.affiliation: Aix-Marseille-Université, CNRS, Institut de Biologie du Développement de Marseille, UMR 7288, case 907, 13288 Marseille Cedex 09, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Lo Re
authors.affiliation: Aix-Marseille-Université, CNRS, Institut de Biologie du Développement de Marseille, UMR 7288, case 907, 13288 Marseille Cedex 09, France.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Mantilleri
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM CR 18, Neuroscience Paris Seine, 75005 Paris, France; Centre National de la Recherche Scientifique (CNRS), UMR 8246 Paris, France; Institut national de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130 Paris, France.
authors.forename: Régine
authors.initials: R
authors.lastname: Hepp
authors.affiliation: Aix-Marseille-Université, CNRS, Institut de Biologie du Développement de Marseille, UMR 7288, case 907, 13288 Marseille Cedex 09, France.
authors.forename: Louise
authors.initials: L
authors.lastname: Urien
authors.affiliation: Aix-Marseille-Université, CNRS, Institut de Biologie du Développement de Marseille, UMR 7288, case 907, 13288 Marseille Cedex 09, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Malapert
authors.affiliation: Aix-Marseille-Université, CNRS, Institut de Biologie du Développement de Marseille, UMR 7288, case 907, 13288 Marseille Cedex 09, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Alonso
authors.affiliation: Laboratories of Excellence, Ion Channel Science and Therapeutics, Institut de Génomique Fonctionnelle, UMR 5203, CNRS, U661, INSERM, Universités Montpellier I&II, 141 Rue de la Cardonille, 34094 Montpellier Cedex 05, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Deage
authors.affiliation: University Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France; CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France.
authors.forename: Charline
authors.initials: C
authors.lastname: Kambrun
authors.affiliation: University Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France; CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Landry
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Stanford Neurosciences Institute, Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Low
authors.affiliation: Laboratoire de Pharmacologie Médicale, Faculté de Médecine et de Pharmacie, UMR 766 INSERM, 28 place Henri-Dunant, BP 38, 63001 Clermont-Ferrand Cedex 1, France.
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Alloui
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM CR 18, Neuroscience Paris Seine, 75005 Paris, France; Centre National de la Recherche Scientifique (CNRS), UMR 8246 Paris, France; Institut national de la Santé et de la Recherche Médicale (INSERM), UMR-S 1130 Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Lambolez
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Stanford Neurosciences Institute, Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Grégory
authors.initials: G
authors.lastname: Scherrer
authors.affiliation: University Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France; CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Feuvre
authors.affiliation: Laboratories of Excellence, Ion Channel Science and Therapeutics, Institut de Génomique Fonctionnelle, UMR 5203, CNRS, U661, INSERM, Universités Montpellier I&II, 141 Rue de la Cardonille, 34094 Montpellier Cedex 05, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bourinet
authors.affiliation: Aix-Marseille-Université, CNRS, Institut de Biologie du Développement de Marseille, UMR 7288, case 907, 13288 Marseille Cedex 09, France. Electronic address: aziz.moqrich@univ-amu.fr.
authors.forename: Aziz
authors.initials: A
authors.lastname: Moqrich
mesh_terms: D000595:Amino Acid Sequence; D000698:Analgesia / Q000379:methods*; D000818:Animals; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D018080:Receptors, GABA-B / Q000502:physiology*
chemical_list: D018080:Receptors, GABA-B; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D019206:GTP-Binding Protein alpha Subunits, Gi-Go