Nerve Injury Evoked Loss of Latexin Expression in Spinal Cord Neurons Contributes to the Development of Neuropathic Pain

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.

Proteomic Modulation in the Dorsal Spinal Cord Following Spinal Cord Stimulation Therapy in an In Vivo Neuropathic Pain Model

“…Proteomic data from five studies show a combined 538 proteins found to be significantly modulated by the SNI model (4, 5, 28–30) (Supplementary Table S2). Of the 155 proteins found to be significantly affected by SCS therapy, 33 overlap with the 538 proteins identified in literature as affected by the injury model.…”

Temporal and Qualitative Differences in the Development of Allodynic Behaviors between Mice and Rats in a Peripheral Nerve Injury Model

“…Anesthesia type may not be the strongest factor for the observed differences because even though the first mouse SNI study indicates that the use of Ketamine and Xylazine precludes the development of mechanical hypersensitivity [7], several studies have used this exact cocktail and showed that mechanical hyperalgesia and allodynia develop immediately after the injury in C57BL/6 mice [12] [13]. In the acetone test for cold allodynia, the majority of papers either do not define a particular volume that is applied to the paws, or report a range of volumes, making reproducibility difficult [14]- [16]. Care must be taken in the acetone drop test because there may be a mechanical stimulation component if syringe tips touch the paws, or if the "spray" of acetone is too forceful.…”

Research progress on combat trauma treatment in cold regions

“…With prolonged cold exposure, human motor and sensory neurons are also functionally suppressed, which leads to numbness and irreversible damages [ 3 ]. Kühlein et al [ 4 ] experimentally demonstrated that cold injury can slow cranial nerve transduction and may indirectly intensify cold injury via oxidative damage, inducing brain edema, secondary brain injury, and apoptosis. Every 1°C reduction in body temperature corresponds to a decrease in cerebral blood flow by 6%-7%, which can endanger the lives of patients sustaining traumatic brain injury.…”