title: A sensory subpopulation depends on vesicular glutamate transporter 2 for mechanical pain, and together with substance P, inflammatory pain.
abstract: Ablating or functionally compromising sets of sensory neurons has provided important insights into peripheral modality-specific wiring in the somatosensory system. Inflammatory hyperalgesia, cold pain, and noxious mechanosensation have all been shown to depend upon Na(v)1.8-positive sensory neurons. The release of fast-acting neurotransmitters, such as glutamate, and more slowly released neuropeptides, such as substance P (SP), contribute to the diversified responses to external stimuli. Here we show that deleting Vglut2 in Na(v)1.8(Cre)-positive neurons compromised mechanical pain and NGF-induced thermal hyperalgesia, whereas tactile-evoked sensation, thermal, formalin-evoked, and chronic neuropathic pain were normal. However, when Vglut2(f/f);Na(v)1.8(Cre) mice were injected with a SP antagonist before the formalin test, the second phase pain response was nearly completely abolished, whereas in control mice, the pain response was unaffected. Our results suggest that VGLUT2-dependent signaling originating from Na(v)1.8-positive neurons is a principal sensing mechanism for mechanical pain and, together with SP, inflammatory pain. These data define sets of primary afferents associated with specific modalities and provide useful genetic tools with which to analyze the pathways that are activated by functionally distinct neuronal populations and transmitters.
authors.affiliation: Department of Neuroscience, Uppsala University, 75124 Uppsala, Sweden.
authors.forename: Malin C
authors.initials: MC
authors.lastname: Lagerström
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Rogoz
authors.forename: Bjarke
authors.initials: B
authors.lastname: Abrahamsen
authors.forename: Anne-Li
authors.initials: AL
authors.lastname: Lind
authors.forename: Caroline
authors.initials: C
authors.lastname: Olund
authors.forename: Casey
authors.initials: C
authors.lastname: Smith
authors.forename: José Alfredo
authors.initials: JA
authors.lastname: Mendez
authors.forename: Åsa
authors.initials: Å
authors.lastname: Wallén-Mackenzie
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Klas
authors.initials: K
authors.lastname: Kullander
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017931:DNA Primers / Q000235:genetics; D005838:Genotype; D006930:Hyperalgesia / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008959:Models, Neurological; D010146:Pain / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism*; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D013373:Substance P