VGLUT2-dependent glutamatergic transmission in primary afferents is required for intact nociception in both acute and persistent pain modalities.
Glutamate is an essential transmitter in pain pathways. However, its broad usage in the central and peripheral nervous system prevents us from designing efficient glutamate-based pain therapies without causing harmful side effects. The discovery of vesicular glutamate transporters (VGLUT1-3) has been a crucial step in describing specific glutamatergic neuronal subpopulations and glutamate-dependent pain pathways. To assess the role of VGLUT2-mediated glutamatergic contribution to pain transmission from the entire primary sensory population, we crossed our Vglut2(f/f) line with the Ht-Pa-Cre line. Such Vglut2-deficient mice showed significantly decreased, but not completely absent, acute nociceptive responses. The animals were less prone to develop an inflammatory-related state of pain and were, in the partial sciatic nerve ligation chronic pain model, much less hypersensitive to mechanical stimuli and did not develop cold allodynia or heat hyperalgesia. To take advantage of this neuropathic pain-resistant model, we analyzed Vglut2-dependent transcriptional changes in the dorsal spinal cord after nerve injury, which revealed several novel candidate target genes potentially relevant for the development of neuropathic pain therapeutics. Taken together, we conclude that VGLUT2 is a major mediator of nociception in primary afferents, implying that glutamate is the key somatosensory neurotransmitter.
Department of Neuroscience, Uppsala University, Uppsala, Sweden UMR 144 Compartimentation et Dynamique Cellulaire Centre National de la Recherche Scientifique et Institut Curie, Paris Cedex 05, France.
Katarzyna
K
Rogoz
Malin C
MC
Lagerström
Sylvie
S
Dufour
Klas
K
Kullander
D059787:Acute Pain / Q000378:metabolism*; D000818:Animals; D059350:Chronic Pain / Q000378:metabolism*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000503:physiopathology; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism*; D059225:Nociception / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism*
C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2