Abstract
Neuropathic pain is still an extremely important problem in today’s medicine because opioids, which are commonly used to reduce pain, have limited efficacy in this type of pathology. Therefore, complementary therapy is needed. Our experiments were performed in rats to evaluate the contribution of the purinergic system, especially P2X4 receptor (P2X4R), in the modulation of glia activation and, consequently, the levels of nociceptive interleukins after chronic constriction injury (CCI) of the right sciatic nerve, a rat model of neuropathic pain. Moreover, we studied how intrathecal (ith.) injection of a P2X4R antagonist Tricarbonyldichlororuthenium (II) dimer (CORM-2) modulates nociceptive transmission and opioid effectiveness in the CCI model. Our results demonstrate that repeated ith. administration of CORM-2 once daily (20 μg/5 μl, 16 and 1 h before CCI and then daily) for eight consecutive days significantly reduced pain-related behavior and activation of both spinal microglia and/or astroglia induced by CCI. Moreover, even a single administration of CORM-2 on day 7 after CCI attenuated mechanical and thermal hypersensitivity as efficiently as morphine and buprenorphine. In addition, using Western blot, we have shown that repeated ith. administration of CORM-2 lowers the CCI-elevated level of MMP-9 and pronociceptive interleukins (IL-1β, IL-18, IL-6) in the dorsal L4-L6 spinal cord and/or DRG. Furthermore, in parallel, CORM-2 upregulates spinal IL-1Ra; however, it does not influence other antinociceptive factors, IL-10 and IL-18BP. Additionally, based on our biochemical results, we hypothesize that p38MAPK, ERK1/2 and PI3K/Akt but not the NLRP3/Caspase-1 pathway are partly involved in the CORM-2 analgesic effects in rat neuropathic pain. Our data provide new evidence that P2X4R may indeed play a significant role in neuropathic pain development by modulating neuroimmune interactions in the spinal cord and DRG, suggesting that its blockade may have potential therapeutic utility.
Highlights
The neuropathic pain state, which can occur after injury of a nerve or be a concurrent symptom of various clinical disorders, is considered to be one of the most important problems in medicine today (Burma et al, 2016; Burke et al, 2017)
Upregulation of P2X4 receptor (P2X4R) levels in the spinal cord was significant at every time point, but there was no change in the DRG (Figure 1B) after constriction injury (CCI) comparing to INTACT group
CORM-2 did not influence the level of P2X4R in the spinal cord (Figure 2D) or DRG (Figure 2E) which was respectively: elevated and unchanged comparing to INTACT group
Summary
The neuropathic pain state, which can occur after injury of a nerve or be a concurrent symptom of various clinical disorders, is considered to be one of the most important problems in medicine today (Burma et al, 2016; Burke et al, 2017). A rising number of reports have confirmed the crucial role of microglial cells in neuropathic pain development (Tsuda et al, 2003; Beggs and Salter, 2013). Those cells have been shown to be strongly activated after peripheral nerve injury on the ipsilateral side of the spinal cord (Tsuda et al, 2003; Beggs and Salter, 2013). As well as other laboratories, have previously reported that inhibiting microglia activation with minocycline significantly reduces pain behavior and the level of pronociceptive interleukins and enhances the effectiveness of morphine in neuropathy (Mika et al, 2007; Cui et al, 2008; Zychowska et al, 2016)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
