Journal
PAIN
Volume 125, Issue 1-2, Pages 20-34Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.pain.2006.04.022
Keywords
calcium channels; neuropathic pain; transgenic mice; spinal hyperexcitability
Categories
Funding
- NIDCR NIH HHS [DE14545, R21 DE014545] Funding Source: Medline
- NINDS NIH HHS [NS40135, P01 NS041384, R01 NS040135, NS41384] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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Mechanisms of chronic pain, including neuropathic pain, are poorly understood. Upregulation of voltage-gated calcium channel (VGCC) alpha(2)delta(1) subunit (Cav alpha(2)delta(1)) 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 Cav alpha(2)delta(1) in neuronal tissues. Cav alpha(2)delta(1) 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 alpha(2)delta(1) 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 Cav alpha(2)delta(1) 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. (c) 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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