Journal
JOURNAL OF NEUROSCIENCE
Volume 33, Issue 42, Pages 16412-16426Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1026-13.2013
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Funding
- Medical Research Council United Kingdom [G0801756, G0901758]
- Wellcome Trust [098360/Z/12/Z, 095698/Z/11/Z]
- Biotechnology and Biological Sciences Research Council
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- Wellcome Trust [095698/Z/11/Z] Funding Source: Wellcome Trust
- MRC [G0801756, G0901758, G0700368] Funding Source: UKRI
- Medical Research Council [G0700368, G0901758, G0801756] Funding Source: researchfish
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The alpha(2)delta-1 subunit of voltage-gated calcium channels is upregulated after sensory nerve injury and is also the therapeutic target of gabapentinoid drugs. It is therefore likely to play a key role in the development of neuropathic pain. In this study, we have examined mice in which alpha(2)delta-1 gene expression is disrupted, to determine whether alpha(2)delta-1 is involved in various modalities of nociception, and for the development of behavioral hypersensitivity after partial sciatic nerve ligation (PSNL). We find that naive alpha(2)delta-1(-/-) mice show a marked behavioral deficit in mechanical and cold sensitivity, but no change in thermal nociception threshold. The lower mechanical sensitivity is mirrored by a reduced in vivo electrophysiological response of dorsal horn wide dynamic range neurons. The Ca(V)2.2 level is reduced in brain and spinal cord synaptosomes from alpha(2)delta-1(-/-) mice, and alpha(2)delta-1(-/-) DRG neurons exhibit lower calcium channel current density. Furthermore, a significantly smaller number of DRG neurons respond to the TRPM8 agonist menthol. After PSNL, alpha(2)delta-1(-/-) mice show delayed mechanical hypersensitivity, which only develops at 11 d after surgery, whereas in wild-type littermates it is maximal at the earliest time point measured (3 d). There is no compensatory upregulation of alpha(2)delta-2 or alpha(2)delta-3 after PSNL in alpha(2)delta-1(-/-) mice, and other transcripts, including neuropeptide Y and activating transcription factor-3, are upregulated normally. Furthermore, the ability of pregabalin to alleviate mechanical hypersensitivity is lost in PSNL alpha(2)delta-1(-/-) mice. Thus, alpha(2)delta-1 is essential for rapid development of mechanical hypersensitivity in a nerve injury model of neuropathic pain.
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