Ulinastatin attenuates neuropathic pain induced by L5-VRT via the calcineurin/IL-10 pathway

Abstract

Previous studies have shown that ulinastatin, an effective inhibitor of the inflammatory response in clinical applications, can attenuate hyperalgesia in rodents. However, the underlying mechanism remains unclear. In the present study, we first examined the change in the calcineurin level, which plays an important role in regulating cytokine release in the nervous system, following lumbar 5 ventral root transection in the rat. Furthermore, we determined whether intraperitoneal (i.p.) injection of ulinastatin attenuated pain behavior via inhibition of the calcineurin-mediated inflammatory response induced by lumbar 5 ventral root transection. The results showed that the paw withdrawal threshold and paw withdrawal latency were significantly decreased following lumbar 5 ventral root transection compared to the sham group. Neuropathic pain induced by lumbar 5 ventral root transection significantly decreased the expression of calcineurin in the DRG, and calcineurin was mostly located with NF-200-positive cells, IB4-positive cells, and CGRP-positive cells and less with GFAP-positive satellite cells. Furthermore, intrathecal (i.t.) injection of exogenous calcineurin attenuated the pain behavior induced by lumbar 5 ventral root transection. Importantly, intraperitoneal injection of ulinastatin alleviated the pain behavior and calcineurin downregulation induced by lumbar 5 ventral root transection. Lastly, the cytokine IL-10 was significantly decreased following lumbar 5 ventral root transection, and application of calcineurin (intrathecal) or ulinastatin (intraperitoneal) inhibited the IL-10 downregulation induced by lumbar 5 ventral root transection. These results suggested that ulinastatin, by acting on the CN/IL-10 pathway, might be a novel and effective drug for the treatment of neuropathic pain.

<p>Electroacupuncture treatment upregulates α7nAChR and inhibits JAK2/STAT3 in dorsal root ganglion of rat with spared nerve injury</p>

“…Conversely, IL-10 was regarded as a powerful anti-inflammatory cytokine which exerted its anti-inflammatory effects in neuropathic pain. Such as repeated intrathecal injections of IL-10 could reverse mechanical hypersensitivity induced by neuropathic pain,40 IL-10 obviously reduced the inflammatory response via suppressing pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) at the site of nerve injury, IL-10 protein expression in DRG was significantly down-regulated in lumbar ventral root transection and CCI-induced neuropathic pain 41,42. Consistently, our present data revealed that SNI distinctly induced the up-regulation of IL-1β and IL-6 protein expression in the DRG, and along with the significant down-regulation of IL-10 level, which suggested that the imbalance between pro-inflammatory cytokines IL-1β, IL-6 and anti-inflammatory cytokine IL-10 in DRG contributed to SNI-induced neuropathic pain.…”

Targeting cytokines for treatment of neuropathic pain

“…Administration of exogenous IL-10 alleviates allodynia in animal models of CCI and paclitaxel-induced neuropathic pain [94,95]. Drugs such as calcineurin, uliastatin, plasmid DNA, and viral vector indirectly increase IL-10 concentrations [7,96,97], and may be promising therapeutic targets in the treatment of neuropathic pain.…”

Calcineurin Regulates Synaptic Plasticity and Nociceptive Transmission at the Spinal Cord Level

“…It is mostly present in neurons expressing isolectin B4, calcitonin gene-related peptide, and neurofilament-200. Calcineurin is weakly expressed in glial fibrillary acidic protein-positive satellite cells in the DRG (Ouyang and others 2016). At the subcellular level, about half of calcineurin is cytosolic, and the other half is associated with the plasma membrane.…”