The RS504393 Influences the Level of Nociceptive Factors and Enhances Opioid Analgesic Potency in Neuropathic Rats

Abstract

Increasing evidence has indicated that activated glial cells releasing nociceptive factors, such as interleukins and chemokines, are of key importance for neuropathic pain. Significant changes in the production of nociceptive factors are associated with the low effectiveness of opioids in neuropathic pain. Recently, it has been suggested that CCL2/CCR2 signaling is important for nociception. Here, we studied the time course changes in the mRNA/protein level of CD40/Iba-1, CCL2 and CCR2 in the spinal cord/dorsal root ganglia (DRG) in rats following chronic constriction injury (CCI) of the sciatic nerve. Moreover, we examined the influence of intrathecal preemptive and repeated (daily for 7 days) administration of RS504393, CCR2 antagonist, on pain-related behavior and the associated biochemical changes of some nociceptive factors as well as its influence on opioid effectiveness. We observed simultaneous upregulation of Iba-1, CCL2, CCR2 in the spinal cord on 7th day after CCI. Additionally, we demonstrated that repeated administration of RS504393 not only attenuated tactile/thermal hypersensitivity but also enhanced the analgesic properties of morphine and buprenorphine under neuropathy. Our results proof that repeated administration of RS504393 reduced the mRNA and/or protein levels of pronociceptive factors, such as IL-1beta, IL-18, IL-6 and inducible nitric oxide synthase (iNOS), and some of their receptors in the spinal cord and/or DRG. Furthermore, RS504393 elevated the spinal protein level of antinociceptive IL-1alpha and IL-18 binding protein. Our data provide new evidence that CCR2 is a promising target for diminishing neuropathic pain and enhancing the opioid analgesic effects.

The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain

“…There are many reports showing the morphological changes of activated microglia/macrophages after nerve injury in immunofluorescence studies . We observed, using Western blot analysis, a strong increase in the number of IBA‐1‐positive cells on the 7th day post‐CCI in the spinal cord and the DRG, which is in agreement with other data . Many of these works emphasize that the strong uncontrolled activation of microglia/macrophages is the cause of the development of neuropathic pain.…”

“…After repeated intrathecal J113863 treatment, the spinal level of IL‐18 was decreased. Similar effects have been observed after maraviroc and RS504393 administration in CCI‐exposed rats. Our results indicate that J113863 restores the balance between IL‐18 and IL‐18BP by lowering the spinal level of IL‐18 without affecting the level of IL‐18BP.…”

“…In our study, a CCR1 antagonist reduced spinal microglial/macrophage activation, similarly to other substances that weakened neuropathic pain‐related symptoms, e.g. minocycline, gabapentin, zaprinast, maraviroc (CCR5 antagonist) and RS504393 (CCR2 antagonist) . In turn, the role of GFAP‐positive cells (astroglia and satellite cells) in neuropathy is still unclear, some studies suggest that they can promote protective functions in neuropathic pain .…”

“…We believe that the blockade of CCR1 by J113863, through a reduction in the number of IBA‐1‐positive cells and the consequent restoration of the neuroimmune balance, is one of the main mechanisms of the improved effectiveness of opioids in a CCI model. Similarly, other chemokine receptor antagonists are also able to improve opioid efficacy . The other explanation for better opioid efficacy might be the formation of heterodimers between chemokine receptors and opioid receptors (e.g.…”

“…The transcript level of HPRT (a housekeeping gene) was not significantly altered in the CCI‐exposed rats and therefore served as an adequate control. The RT‐qPCR method was described in our previous studies …”