VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity.
Dorsal root ganglia (DRG) neurons, including the nociceptors that detect painful thermal, mechanical, and chemical stimuli, transmit information to spinal cord neurons via glutamatergic and peptidergic neurotransmitters. However, the specific contribution of glutamate to pain generated by distinct sensory modalities or injuries is not known. Here we generated mice in which the vesicular glutamate transporter 2 (VGLUT2) is ablated selectively from DRG neurons. We report that conditional knockout (cKO) of the Slc17a6 gene encoding VGLUT2 from the great majority of nociceptors profoundly decreased VGLUT2 mRNA and protein in these neurons, and reduced firing of lamina I spinal cord neurons in response to noxious heat and mechanical stimulation. In behavioral assays, cKO mice showed decreased responsiveness to acute noxious heat, mechanical, and chemical (capsaicin) stimuli, but responded normally to cold stimulation and in the formalin test. Strikingly, although tissue injury-induced heat hyperalgesia was lost in the cKO mice, mechanical hypersensitivity developed normally. In a model of nerve injury-induced neuropathic pain, the magnitude of heat hypersensitivity was diminished in cKO mice, but both the mechanical allodynia and the microgliosis generated by nerve injury were intact. These findings suggest that VGLUT2 expression in nociceptors is essential for normal perception of acute pain and heat hyperalgesia, and that heat and mechanical hypersensitivity induced by peripheral injury rely on distinct (VGLUT2 dependent and VGLUT2 independent, respectively) primary afferent mechanisms and pathways.
Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.
Grégory
G
Scherrer
Sarah A
SA
Low
Xidao
X
Wang
Jie
J
Zhang
Hiroki
H
Yamanaka
Rochelle
R
Urban
Carlos
C
Solorzano
Blaine
B
Harper
Thomas S
TS
Hnasko
Robert H
RH
Edwards
Allan I
AI
Basbaum
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D003080:Cold Temperature; D005404:Fixatives / Q000494:pharmacology; D005557:Formaldehyde / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000378:metabolism*; D005786:Gene Expression Regulation; D006358:Hot Temperature; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D018689:Sensory System Agents / Q000494:pharmacology; D050599:Vesicular Glutamate Transport Protein 2 / Q000096:biosynthesis* / Q000235:genetics
D005404:Fixatives; D018689:Sensory System Agents; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D005557:Formaldehyde; D002211:Capsaicin