VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch.
Itch can be suppressed by painful stimuli, but the underlying neural basis is unknown. We generated conditional null mice in which vesicular glutamate transporter type 2 (VGLUT2)-dependent synaptic glutamate release from mainly Nav1.8-expressing nociceptors was abolished. These mice showed deficits in pain behaviors, including mechanical pain, heat pain, capsaicin-evoked pain, inflammatory pain, and neuropathic pain. The pain deficits were accompanied by greatly enhanced itching, as suggested by (1) sensitization of both histamine-dependent and histamine-independent itch pathways and (2) development of spontaneous scratching and skin lesions. Strikingly, intradermal capsaicin injection promotes itch responses in these mutant mice, as opposed to pain responses in control littermates. Consequently, coinjection of capsaicin was no longer able to mask itch evoked by pruritogenic compounds. Our studies suggest that synaptic glutamate release from a group of peripheral nociceptors is required to sense pain and suppress itch. Elimination of VGLUT2 in these nociceptors creates a mouse model of chronic neurogenic itch.
Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, 1 Jimmy Fund Way, Boston, MA 02115, USA.
Yang
Y
Liu
Omar
O
Abdel Samad
Ling
L
Zhang
Bo
B
Duan
Qingchun
Q
Tong
Claudia
C
Lopes
Ru-Rong
RR
Ji
Bradford B
BB
Lowell
Qiufu
Q
Ma
D000208:Acute Disease; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002452:Cell Count; D002908:Chronic Disease; D018698:Glutamic Acid / Q000378:metabolism* / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009434:Neural Pathways / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009619:Nociceptors / Q000378:metabolism* / Q000502:physiology*; D010146:Pain / Q000503:physiopathology* / Q000523:psychology; D018408:Patch-Clamp Techniques; D011537:Pruritus / Q000139:chemically induced / Q000503:physiopathology* / Q000523:psychology; D018004:Receptors, Bombesin / Q000502:physiology; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000502:physiology*
D062559:NAV1.8 Voltage-Gated Sodium Channel; D018004:Receptors, Bombesin; C568318:Scn10a protein, mouse; C493477:Slc17a6 protein, mouse; D015222:Sodium Channels; D050599:Vesicular Glutamate Transport Protein 2; D018698:Glutamic Acid; D002211:Capsaicin