Genetic deletion of synapsin II reduces neuropathic pain due to reduced glutamate but increased GABA in the spinal cord dorsal horn.
The synaptic vesicle protein synapsin II is specifically expressed in synaptic terminals of primary afferent nociceptive neurons and regulates transmitter release in the spinal cord dorsal horn. Here, we assessed its role in nerve injury-evoked molecular and behavioral adaptations in models of peripheral neuropathic pain using mice genetically lacking synapsin II. Deficiency of synapsin II resulted in reduced mechanical and cold allodynia in two models of peripheral neuropathic pain. This was associated with decreased glutamate release in the dorsal horn of the spinal cord upon sciatic nerve injury or capsaicin application onto the sciatic nerve and reduced calcium signals in spinal cord slices upon persistent activation of primary afferents. In addition, the expression of the vesicular glutamate transporters, VGLUT1 and VGLUT2, was strongly reduced in synapsin II knockout mice in the spinal cord. Conversely, synapsin II knockout mice showed a stronger and longer-lasting increase of GABA in lamina II of the dorsal horn after nerve injury than wild type mice. These results suggest that synapsin II is involved in the regulation of glutamate and GABA release in the spinal cord after nerve injury, and that a imbalance between glutamatergic and GABAergic synaptic transmission contributes to the manifestation of neuropathic pain.
Schmidtko
Achim
A
pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe Universität, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany Pharmakologisches Institut, Universität Heidelberg, Germany.
Luo
Ceng
C
Gao
Wei
W
Geisslinger
Gerd
G
Kuner
Rohini
R
Tegeder
Irmgard
I
D051700:Activating Transcription Factor 3 / Q000096:biosynthesis / Q000235:genetics; D000255:Adenosine Triphosphate / Q000502:physiology; D000344:Afferent Pathways / Q000503:physiopathology; D000818:Animals; D020013:Calcium Signaling; D002211:Capsaicin / Q000633:toxicity; D005260:Female; D018698:Glutamic Acid / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D020671:Posterior Horn Cells / Q000378:metabolism / Q000502:physiology*; D012584:Sciatic Nerve / Q000293:injuries; D012585:Sciatica / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology*; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology*; D016704:Synapsins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D016704:Synapsins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000255:Adenosine Triphosphate; D002211:Capsaicin