Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states.
Spinal cord injury (SCI) commonly results in the development of neuropathic pain, which can dramatically impair the quality of life for SCI patients. SCI-induced neuropathic pain can be manifested as both tactile allodynia (a painful sensation to a non-noxious stimulus) and hyperalgesia (an enhanced sensation to a painful stimulus). The mechanisms underlying these pain states are poorly understood. Clinical studies have shown that gabapentin, a drug that binds to the voltage-gated calcium channel alpha-2-delta-1 subunit (Ca(v)α2δ-1) proteins is effective in the management of SCI-induced neuropathic pain. Accordingly, we hypothesized that tactile allodynia post SCI is mediated by an upregulation of Ca(v)α2δ-1 in dorsal spinal cord. To test this hypothesis, we examined whether SCI-induced dysregulation of spinal Ca(v)α2δ-1 plays a contributory role in below-level allodynia development in a rat spinal T9 contusion injury model. We found that Ca(v)α2δ-1 expression levels were significantly increased in L4-6 dorsal, but not ventral, spinal cord of SCI rats that correlated with tactile allodynia development in the hind paw plantar surface. Furthermore, both intrathecal gabapentin treatment and blocking SCI-induced Ca(v)α2δ-1 protein upregulation by intrathecal Ca(v)α2δ-1 antisense oligodeoxynucleotides could reverse tactile allodynia in SCI rats. These findings support that SCI-induced Ca(v)α2δ-1 upregulation in spinal dorsal horn is a key component in mediating below-level neuropathic pain states, and selectively targeting this pathway may provide effective pain relief for SCI patients. Spinal cord contusion injury caused increased calcium channel Ca(v)α2δ-1 subunit expression in dorsal spinal cord that contributes to neuropathic pain states.
Department of Pharmacology, University of California Irvine, School of Medicine, Irvine, CA 92697, USA Department of Anesthesiology & Perioperative Care, University of California Irvine, School of Medicine, Irvine, CA 92697, USA Reeve-Irvine Research Center, University of California Irvine, School of Medicine, Irvine, CA 92697, USA.
Amin
A
Boroujerdi
Jun
J
Zeng
Kelli
K
Sharp
Donghyun
D
Kim
Oswald
O
Steward
David Z
DZ
Luo
D000588:Amines / Q000627:therapeutic use; D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D000077206:Gabapentin; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000150:complications*; D013223:Statistics as Topic; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use
D000588:Amines; D000700:Analgesics; C486060:Cacna2d1 protein, rat; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D003509:Cyclohexanecarboxylic Acids; D020319:Oligodeoxyribonucleotides, Antisense; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin
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