Abstract
Nerve injury leads to sensitization mechanisms in the peripheral and central nervous system which involve transcriptional and post-transcriptional modifications in sensory nerves. To assess protein regulations in the spinal cord after injury of the sciatic nerve in the Spared Nerve Injury model (SNI) we performed a proteomic analysis using 2D-difference gel electrophoresis (DIGE) technology. Among approximately 2300 protein spots separated on each gel we detected 55 significantly regulated proteins after SNI whereof 41 were successfully identified by MALDI-TOF MS. Out of the proteins which were regulated in the DIGE analyses after SNI we focused on the carboxypeptidase A inhibitor latexin because protease dysfunctions contribute to the development of neuropathic pain. Latexin protein expression was reduced after SNI which could be confirmed by Western Blot analysis, quantitative RT-PCR and in-situ hybridisation. The decrease of latexin was associated with an increase of the activity of carboxypeptidase A indicating that the balance between latexin and carboxypeptidase A was impaired in the spinal cord after peripheral nerve injury due to a loss of latexin expression in spinal cord neurons. This may contribute to the development of cold allodynia because normalization of neuronal latexin expression in the spinal cord by AAV-mediated latexin transduction or administration of a small molecule carboxypeptidase A inhibitor significantly reduced acetone-evoked nociceptive behavior after SNI. Our results show the usefulness of proteomics as a screening tool to identify novel mechanisms of nerve injury evoked hypernociception and suggest that carboxypeptidase A inhibition might be useful to reduce cold allodynia.
Highlights
Injury to peripheral or central nerves may result in the development of neuropathic pain [1]
The proteome of spinal cord lumbar dorsal horn samples from Spared Nerve Injury model (SNI) and sham operated rats was analyzed by 2D-difference gel electrophoresis (DIGE)
In concordance with the protein level, we found that mRNAs were down regulated for prohibitin (PHB), Annexin A4 (Anxa4), pyruvate dehydrogenase (PD), ubiquitin carboxyterminal hydrolase (UCH), and latexin (Lxn) 7 days after nerve injury
Summary
Injury to peripheral or central nerves may result in the development of neuropathic pain [1]. Because injured neurons adapt protein degradation and de novo synthesis to prepare for the reorganization of signaling and synaptic functions, proteome analyses from afflicted sites are likely to further unravel the mechanisms and unfavorable regulations which challenge the recovery of balance [5]. In the present study we used the Spared Nerve Injury model of neuropathic pain [6] to screen for proteomic manifestations in the spinal cord. It is likely that a dys-balance between carboxypeptidase A and its inhibitor, latexin may affect neuropeptide signaling in the spinal cord. Based on our hypothesis and based on previous evidence we analyzed here the regulation and function of latexin in the spinal cord and dorsal root ganglia in the context of neuropathic pain
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