Beneficial properties of maraviroc on neuropathic pain development and opioid effectiveness in rats

Targeting chemokine signaling pathways is crucial in neuropathy development. In this study, we investigated the influence of chronic administration of maraviroc (CCR5 antagonist) on nociception and opioid effectiveness during neuropathy, which develops as a result of chronic constriction injury (CCI) of the sciatic nerve. To investigate the mechanism of action of maraviroc, we measured the expression of glial cell markers, CCR5 and certain CCR5 ligands (CCL3, CCL4, CCL5, CCL7, CCL11), in the spinal cord and dorsal root ganglia (DRG) of vehicle- and maraviroc-treated, CCI-exposed rats. Our results demonstrate that chronic intrathecal administration of maraviroc diminished neuropathic pain symptoms on day 7 post-CCI. Western blot analysis showed that maraviroc diminished protein level of Iba-1 and GFAP and reversed the up-regulated CCR5 expression observed in spinal cord and DRG after CCI. Additionally, using qRT-PCR, we demonstrated that CCR5 and some of its pronociceptive ligands (CCL3, CCL4, CCL5) increased in the spinal cord after nerve injury, and maraviroc effectively diminished those changes. However, CCL11 spinal expression was undetectable, even after injury. In vitro primary culture studies showed that CCL3, CCL4, CCL5 and CCL7 (but not CCL11) were of microglial and astroglial origin and were up-regulated after LPS stimulation. Our results indicate that maraviroc not only attenuated the development of neuropathic pain symptoms due to significant modulation of neuroimmune interactions but also intensified the analgesic properties of morphine and buprenorphine. In sum, our results suggest the pharmacological modulation of CCR5 by maraviroc as a novel therapeutic approach for co-treatment of patients receiving opioid therapy for neuropathy.