Background/Objectives: Neuropathic pain is one of the most severe types of chronic pain. Although it is difficult to manage, it often co-occurs with depression. Yet, no medication addresses the neuropathic pain and depression comorbidity. Therefore, developing integrated treatment strategies that address both pain and depression is a major public health priority and an unmet need affecting millions. Methods: In this study, we investigated the effect of combining a terpene, Beta-Caryophyllene (BCP), and cannabidiol (CBD) on neuropathic pain and associated depression. We employed a chronic constriction injury (CCI) neuropathic pain model and a series of behavioral tests to evaluate how oral administration of this combination influences neuropathic pain and depression-like behaviors in mice. We employed immunohistochemistry and proteomics approaches to explore the mechanism. Results: The analgesic effect of combining CBD and BCP is synergistic in neuropathic pain and also shows an antidepressant effect. Additionally, we found that this combination decreases neuroinflammation associated with CCI and affects specific genes involved in the inflammation. Conclusions: This work provides preclinical scientific evidence supporting the potential usefulness of this combination for neuropathic pain and associated depression.

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.

Animal models are critical for elucidating disease mechanisms and pathological outcomes, and for evaluating therapeutic interventions. Osteoarthritis (OA) is a leading cause of chronic pain and disability globally. Clinically, individuals with OA experience both sensory and ongoing pain. However, ongoing pain, as assessed by the Mouse Grimace Scale (MGS), has not yet been evaluated in animal models of OA. This study aims to address this significant knowledge gap. We induced OA by intra-articular injection of monosodium iodoacetate (MIA), while control mice received saline injections. We assessed pain behaviors using the MGS on days 1, 3, 7, and 14 after MIA administration. MIA-treated mice exhibited significantly higher MGS scores than saline-treated controls throughout the study period, indicating ongoing pain-related behavior in the MIA OA model. Furthermore, longitudinal studies showed that this pain is chronic, as seen in people with OA. These findings support the usefulness of the MGS test in the MIA model for studying ongoing pain.