Injury type-specific calcium channel alpha 2 delta-1 subunit up-regulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin.
The calcium channel alpha2delta-1 subunit is a structural subunit important for functional calcium channel assembly. In vitro studies have shown that this subunit is the binding site for gabapentin, an anticonvulsant that exerts antihyperalgesic effects by unknown mechanisms. Increased expression of this subunit in the spinal cord and dorsal root ganglia (DRG) has been suggested to play a role in enhanced nociceptive responses of spinal nerve-injured rats to innocuous mechanical stimulation (allodynia). To investigate whether a common mechanism underlies allodynic states derived from different etiologies, and if so, whether similar alpha2delta-1 subunit up-regulation correlates with these allodynic states, we compared DRG and spinal cord alpha2delta-1 subunit levels and gabapentin sensitivity in allodynic rats with mechanical nerve injuries (sciatic nerve chronic constriction injury, spinal nerve transection, or ligation), a metabolic disorder (diabetes), or chemical neuropathy (vincristine neurotoxicity). Our data indicated that even though allodynia occurred in all types of nerve injury investigated, DRG and/or spinal cord alpha2delta-1 subunit up-regulation and gabapentin sensitivity only coexisted in the mechanical and diabetic neuropathies. Thus, induction of the alpha2delta-1 subunit in the DRG and spinal cord is likely regulated by factors that are specific for individual neuropathies and may contribute to gabapentin-sensitive allodynia. However, the calcium channel alpha2delta-1 subunit is not the sole molecular change that uniformly characterizes the neuropathic pain states.
Luo
Z D
ZD
Department of Anesthesiology, University of California San Diego, La Jolla, California 92093-0818, USA. zluo@ucsd.edu
Calcutt
N A
NA
Higuera
E S
ES
Valder
C R
CR
Song
Y-H
YH
Svensson
C I
CI
Myers
R R
RR
D000085:Acetates / Q000494:pharmacology* / Q000627:therapeutic use; D000588:Amines; D000818:Animals; D015220:Calcium Channels / Q000096:biosynthesis*; D003509:Cyclohexanecarboxylic Acids; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D000077206:Gabapentin; D005727:Ganglia, Spinal / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D006801:Humans; D008026:Ligation; D008297:Male; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D021122:Protein Subunits; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D021122:Protein Subunits; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin