VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch.
The natural response to itch sensation is to scratch, which relieves the itch through an unknown mechanism. Interaction between pain and itch has been frequently demonstrated, and the selectivity hypothesis of itch, based on data from electrophysiological and behavioral experiments, postulates the existence of primary pain afferents capable of repressing itch. Here, we demonstrate that deletion of vesicular glutamate transporter (VGLUT) 2 in a subpopulation of neurons partly overlapping with the vanilloid receptor (TRPV1) primary afferents resulted in a dramatic increase in itch behavior accompanied by a reduced responsiveness to thermal pain. The increased itch behavior was reduced by administration of antihistaminergic drugs and by genetic deletion of the gastrin-releasing peptide receptor, demonstrating a dependence on VGLUT2 to maintain normal levels of both histaminergic and nonhistaminergic itch. This study establishes that VGLUT2 is a major player in TRPV1 thermal nociception and also serves to regulate a normal itch response.
Department of Neuroscience, Uppsala University, Box 593, 751 24 Uppsala, Sweden.
Malin C
MC
Lagerström
Katarzyna
K
Rogoz
Bjarke
B
Abrahamsen
Emma
E
Persson
Björn
B
Reinius
Karin
K
Nordenankar
Caroline
C
Olund
Casey
C
Smith
José Alfredo
JA
Mendez
Zhou-Feng
ZF
Chen
John N
JN
Wood
Asa
A
Wallén-Mackenzie
Klas
K
Kullander
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D005260:Female; D006632:Histamine / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D062559:NAV1.8 Voltage-Gated Sodium Channel; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement; D010812:Physical Stimulation; D010960:Plasminogen Activators / Q000502:physiology; D011537:Pruritus / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D015222:Sodium Channels / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D050916:TRPV Cation Channels / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000502:physiology; D050599:Vesicular Glutamate Transport Protein 2 / Q000502:physiology*
D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C493476:SLC17A6 protein, human; C568318:Scn10a protein, mouse; D015222:Sodium Channels; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D050599:Vesicular Glutamate Transport Protein 2; D006632:Histamine; D014446:Tyrosine 3-Monooxygenase; D010960:Plasminogen Activators