Endocannabinoid system and HIV-related neuropathic pain

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PROJECT SUMMARY/ABSTRACT Human Immunodeficiency Virus-1 (HIV)-related chronic neuropathic pain affects a majority (55-67%) of the 38 million infected individuals worldwide. Despite the ability of current anti-retroviral therapy (ART) to limit the progression of HIV to AIDS, HIV-positive individuals continue to experience neuropathic pain. Treatment options are limited, often ineffective, and adverse side effects are common. Although therapeutic use (self-medication) of cannabis by HIV-infected people is growing in addition to an interest in the possible medicinal use of cannabis, particularly for pain management, to date, there are no data on whether and how the endocannabinoid system (eCB) is regulated in the HIV-related chronic neuropathic pain. For example, is eCB system functional and effective in controlling neuropathic pain, or impaired in the context of HIV-related neuropathic pain? Moreover, whether and how the exposure to cannabinoids affects the components of the eCB system in this condition is still unknown. This CEBRA research project is designed to address this knowledge gap to provide critical directions for the field of eCB and HIV research in the ART era. Our central hypothesis is that in the ART era, the eCB system remains functional and effective in HIV-related chronic neuropathic pain. To test this hypothesis a comprehensive multidisciplinary approach including behavioral, pharmacological, molecular biology, biochemistry, and Liquid Chromatograph Mass Spectrometry assays will be used. We will use the HIV transgenic rats (HIV-tg) neuropathic model that mimics the HIV chronic condition in the ART era. Aim 1 will perform the first preclinical studies to characterize the status of the eCB system (e.g., endogenous ligands, enzymes involved in eCB metabolism, and CB receptors) in the key areas involved in pain control in the HIV-tg neuropathic model. The components of the eCB system will be analyzed for gene and proteins expression patterns, signaling, levels of endogenous cannabinoids and/or activity enzymatic. Aim 2 will determine the effect (acute and chronic) of clinically relevant cannabinoid agonists with different pharmacological profiles) on neuropathic pain-like behaviors and eCBs in the HIV-tg model. We will use behavioral assessments of sensory and aversive qualities of pain in HIV-tg to test the analgesic effects of these cannabinoids. Additionally, we will also monitor for cannabinoid side effects. The proposed studies will significantly advance the fields of HIV chronic pain management and cannabinoids in the ART era by providing a critical and fundamental new knowledge of the eCB system status in HIV-related chronic neuropathic pain. The novel concept that eCB system is functional and effective in this HIV chronic condition would pave the way for clinically relevant research on cannabinoid-based mechanisms and strategies in HIV-related chronic neuropathic pain in the ART era.