Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain.
Previous studies have shown that peripheral nerve injury in rats induces increased expression of the voltage gated calcium channel (VGCC) alpha-2-delta-1 subunit (Ca v alpha2 delta1) in spinal dorsal horn and sensory neurons in dorsal root ganglia (DRG) that correlates to established neuropathic pain states. To determine if injury discharges trigger Ca v alpha2 delta1 induction that contributes to neuropathic pain initiation, we examined allodynia onset and Ca v alpha2 delta1 levels in DRG and spinal dorsal horn of spinal nerve ligated rats after blocking injury induced neural activity with a local brief application of lidocaine on spinal nerves before the ligation. The lidocaine pretreatment blocked ligation-induced discharges in a dose-dependent manner. Similar pretreatment with the effective concentration of lidocaine diminished injury-induced increases of the Ca v alpha2 delta1 in DRG and abolished that in spinal dorsal horn specifically, and resulted in a delayed onset of tactile allodynia post-injury. Both dorsal horn Ca v alpha2 delta1 upregulation and tactile allodynia in the lidocaine pretreated rats returned to levels similar to that in saline pretreated controls 2 weeks post the ligation injury. In addition, preemptive intrathecal Ca v alpha2 delta1 antisense treatments blocked concurrently injury-induced allodynia onset and Ca v alpha2 delta1 upregulation in dorsal spinal cord. These findings indicate that injury induced discharges regulate Ca v alpha2 delta1 expression in the spinal dorsal horn that is critical for neuropathic allodynia initiation. Thus, preemptive blockade of injury-induced neural activity or Ca v alpha2 delta1 upregulation may be a beneficial option in neuropathic pain management.
Department of Pharmacology, University of California Irvine, Irvine, CA 92697, USA Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA Department of Anesthesiology, University of California Irvine, Irvine, CA 92697, USA.
Amin
A
Boroujerdi
Hee Kee
HK
Kim
Yeoung Su
YS
Lyu
Doo-Sik
DS
Kim
Katherine W
KW
Figueroa
Jin Mo
JM
Chung
David Z
DZ
Luo
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D006930:Hyperalgesia / Q000503:physiopathology*; D008297:Male; D009437:Neuralgia / Q000503:physiopathology*; D020671:Posterior Horn Cells / Q000503:physiopathology*; D021122:Protein Subunits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000293:injuries* / Q000503:physiopathology*; D015854:Up-Regulation
C512066:CACNA2D1 protein, mouse; D015220:Calcium Channels; D021122:Protein Subunits