Repurposing of Maraviroc for the treatment of neuropathic pain

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SUMMARY/ABSTRACT Chronic pain is one of the most common health problems in adult and has profound impact on physical as well as mental wellbeing. According to CDC data brief in 2020, 20.4% of adults in the U.S. have chronic pain. The prevalence is even higher in veterans. Among Veterans receiving primary care in VA healthcare facilities, as many as 50% of male veterans and as many as 75% of female veterans report the presence of pain. In a sample of OEF and OIF veterans, approximately 47% reported at least a mild level of pain and 28% reported moderate to severe pain intensity. Chronic pain is often associated with limitation in mobility and daily activities and frequently comorbid with opioids dependency, anxiety and depression. Current available treatments medications such as NSAIDs, antiepileptic drugs, tricyclic antidepressants, corticosteroids, opioids, and cannabinoids are associated with a range of negative side effects. Invasive and surgical procedures such as peripheral nerve blockers, epidural steroid injections and neural stimulations are also used to provide effective pain relief. The long-term use of these medications often increases the potential for adverse or side effects. Thus, there is urgent needs to develop novel, efficacious and safe interventions for treating neuropathic pain. It is well established that chronic pain, such as inflammation pain, neuropathic pain, and cancer pain, is an expression of neural plasticity both in the peripheral nervous system (PNS) and in the central nervous system (CNS). A large body of evidence indicates that proinflammatory cytokines and chemokines make important contributions to the initiation and persistence of pain. Preliminary studies in our lab using a spared nerve injury (SNI) mouse model of neuropathic pain showed increased expression of CCL5 in the blood and pain phenotypes are significantly correlated with peripheral levels of CCL5. Moreover, analysis of CNS showed increased expression of CCL5 and CCR5 in the brain in the SNI mice, suggesting that CCL5/CCR5 axis may contribute to nerve injury-induced neuropathic pain. In humans, CCL5 was reported to be upregulated in patients with various pain conditions including atypical facial pain and trigeminal neuralgia, discogenic back pain and small fiber neuropathy, indicating its clinical significance in pain development. Based on these observations, we hypothesize that injury-induced increase of CCL5 and its interaction with CCR5 in the periphery and the CNS may dysregulate neural plasticity and promotes the development and persistency of pain. We propose to pharmacologically target CCL5/CCR5 using FDA approved CCR5 antagonist maraviroc in the SNI mouse mode, and use a battery of neurobehavioral tests, immunological and molecular techniques to test its efficacy and to investigate underlying mechanisms. We believe our approach will greatly enhance our understanding of the contribution of CCL5/CCR5 in chronic pain and the potential benefits of targeting CCL5/CCR5 axis as novel therapeutic intervention.