| First Author | Patel R | Year | 2013 |
| Journal | J Neurosci | Volume | 33 |
| Issue | 42 | Pages | 16412-26 |
| PubMed ID | 24133248 | Mgi Jnum | J:202748 |
| Mgi Id | MGI:5521408 | Doi | 10.1523/JNEUROSCI.1026-13.2013 |
| Citation | Patel R, et al. (2013) alpha2delta-1 gene deletion affects somatosensory neuron function and delays mechanical hypersensitivity in response to peripheral nerve damage. J Neurosci 33(42):16412-26 |
| abstractText | The alpha2delta-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 alpha2delta-1 gene expression is disrupted, to determine whether alpha2delta-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 alpha2delta-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 CaV2.2 level is reduced in brain and spinal cord synaptosomes from alpha2delta-1(-/-) mice, and alpha2delta-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, alpha2delta-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 alpha2delta-2 or alpha2delta-3 after PSNL in alpha2delta-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 alpha2delta-1(-/-) mice. Thus, alpha2delta-1 is essential for rapid development of mechanical hypersensitivity in a nerve injury model of neuropathic pain. |
