Calcium channel alpha2delta1 subunit mediates spinal hyperexcitability in pain modulation.
Mechanisms of chronic pain, including neuropathic pain, are poorly understood. Upregulation of voltage-gated calcium channel (VGCC) alpha2delta1 subunit (Ca(v)alpha2delta1) in sensory neurons and dorsal spinal cord by peripheral nerve injury has been suggested to contribute to neuropathic pain. To investigate the mechanisms without the influence of other injury factors, we have created transgenic mice that constitutively overexpress Ca(v)alpha2delta1 in neuronal tissues. Ca(v)alpha2delta1 overexpression resulted in enhanced currents, altered kinetics and voltage-dependence of VGCC activation in sensory neurons; exaggerated and prolonged dorsal horn neuronal responses to mechanical and thermal stimulations at the periphery; and pain behaviors. However, the transgenic mice showed normal dorsal horn neuronal responses to windup stimulation, and behavioral responses to tissue-injury/inflammatory stimuli. The pain behaviors in the transgenic mice had a pharmacological profile suggesting a selective contribution of elevated Ca(v)alpha2delta1 to the abnormal sensations, at least at the spinal cord level. In addition, gabapentin blocked VGCC currents concentration-dependently in transgenic, but not wild-type, sensory neurons. Thus, elevated neuronal Ca(v)alpha2delta1 contributes to specific pain states through a mechanism mediated at least partially by enhanced VGCC activity in sensory neurons and hyperexcitability in dorsal horn neurons in response to peripheral stimulation. Modulation of enhanced VGCC activity by gabapentin may underlie at least partially its antihyperalgesic actions.
Li
Chun-Ying
CY
Department of Anesthesiology, School of Medicine, University of California Irvine, Irvine, CA 92697, USA.
Zhang
Xiu-Lin
XL
Matthews
Elizabeth A
EA
Li
Kang-Wu
KW
Kurwa
Ambereen
A
Boroujerdi
Amin
A
Gross
Jimmy
J
Gold
Michael S
MS
Dickenson
Anthony H
AH
Feng
Guoping
G
Luo
Z David
ZD
D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000503:physiopathology*; D006930:Hyperalgesia / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D010146:Pain / Q000503:physiopathology*; D017288:Pain Threshold; D020671:Posterior Horn Cells / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*
D015220:Calcium Channels; D021122:Protein Subunits