Studying Peripheral Neuropathy and Associated Neuropathic Pain in HIV-1 Transgenic Rats: Evaluation of the Therapeutic Effect of Cannabidiol and Beta-Caryophyllene

Background/Objectives: Peripheral neuropathy affects up to 50% of people living with HIV (PLWH). Currently, no small translational rodent model accurately replicates the peripheral neuropathy observed in PLWH. The primary objectives of this study are to assess whether HIV transgenic (HIV-tg) rats develop peripheral neuropathy with pathological and pain-like behaviors similar to those observed in PLWH and to evaluate the analgesic effects of the non-psychoactive cannabis compounds cannabidiol (CBD) and β-caryophyllene (BCP) in HIV-related neuropathic pain. Methods: We used a comprehensive set of behavioral, pharmacological, molecular, biochemical, and proteomic approaches. Results: Tissue analyses showed that HIV-tg rats had significantly reduced intra-epidermal nerve fiber density and increased macrophage infiltration in the dorsal root ganglion compared with control wild-type rats. Behavioral assessments demonstrated that HIV-tg rats developed mechanical allodynia and ongoing pain. β-caryophyllene (BCP) demonstrated higher efficacy than cannabidiol (CBD) in alleviating HIV-related neuropathic pain. Proteomic analysis identified specific proteins uniquely modulated by the analgesic effects of BCP compared to vehicle in HIV-tg rats with peripheral neuropathy and neuropathic pain. Conclusions: The findings indicate that HIV-tg rats develop peripheral neuropathy and neuropathic pain comparable to those observed in PLWH. BCP is more effective than cannabidiol (CBD) in alleviating HIV-related neuropathic pain. Furthermore, the data suggest that BCP modulates specific proteins that may contribute to its analgesic effects in the HIV-tg model of neuropathic pain, without inducing central side effects.