The endocannabinoid system plays an important role in the intake of palatable food. For example, endocannabinoid signaling in the upper small-intestinal epithelium is increased (i) in rats after tasting dietary fats, which promotes intake of fats, and (ii) in a mouse model of diet-induced obesity, which promotes overeating via impaired nutrient-induced gut–brain satiation signaling. We now utilized a combination of genetic, pharmacological, and behavioral approaches to identify roles for cannabinoid CB₁Rs in upper small-intestinal epithelium in preferences for a western-style diet (WD, high-fat/sucrose) versus a standard rodent diet (SD, low-fat/no sucrose). Mice were maintained on SD in automated feeding chambers. During testing, mice were given simultaneous access to SD and WD, and intakes were recorded. Mice displayed large preferences for the WD, which were inhibited by systemic pretreatment with the cannabinoid CB₁R antagonist/inverse agonist, AM251, for up to 3 h. We next used our novel intestinal epithelium-specific conditional cannabinoid CB₁R-deficient mice (IntCB₁−/−) to investigate if intestinal CB₁Rs are necessary for WD preferences. Similar to AM251 treatment, preferences for WD were largely absent in IntCB₁−/− mice when compared to control mice for up to 6 h. Together, these data suggest that CB₁Rs in the murine intestinal epithelium are required for acute WD preferences.

Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neuroinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized that TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. EcoHIV-infected wildtype (WT) and TREM2^R47H mutant mice were used to study HIV’s impact on TREM2 and behavior. TREM2 and related gene expressions were examined in monocyte-derived macrophages (MDMs) from PWH (n = 42) and people without HIV (PWoH; n = 19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2^R47H mice, with increased IBA1 protein in TREM2^R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not in PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed the upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially reversed by CBD. These findings suggest HIV affects TREM2 expression modulated by cannabis and CBD, offering insights for therapeutic strategies.

Chronic and acute pain are major comorbidities of sickle cell disease (SCD). Both peripheral and central nervous system mechanisms underlie SCD pain. We investigated the potential roles of endogenous fatty acyl derivatives with endocannabinoid-like activity; using targeted lipidomics of fatty acid ethanolamides and monoacylglycerols, we observed significant reduction of spinal palmitoylethanolamide (PEA) in the humanized, transgenic sickle (HbSS)–BERK mouse model of SCD when compared with healthy HbAA control mice. PEA is a paracannabinoid lipid mediator that acts as a putative mast cell stabilizer and has been evaluated clinically for mechanical, cold, and joint pain, which are all features of SCD pain. Increased p38-MAPK activity in the spinal cord and dorsal root ganglia (DRG) neurons, and cutaneous mast cell activation, contribute to chronic hyperalgesia in sickle cell mice. We provide the first evidence that inhibiting endogenous PEA degradation and administration of exogenous PEA, reduces measures of chronic hyperalgesia via inhibition of peripheral and central mechanisms of pain hypersensitivity in sickle cell mice. PEA alleviated spinal inflammation, oxidative stress, and p38-MAPK activity; in the periphery, inhibited p38-MAPK phosphorylation and nuclear translocation in DRG neurons, reduced mast cell extracellular trap formation, and markers of inflammation in HbSS mice. In addition, PEA treatment prevented and ameliorated acute hyperalgesia incited by hypoxia/reoxygenation challenge in sickle cell mice. Pain may persist even after hydroxyurea and curative therapies in SCD. PEA displayed safety in several clinical studies and has the translational potential to treat pain in SCD without the burden of additional medications.

Background/Objectives: HIV-associated neurocognitive impairment (NCI) remains a prevalent issue among people with HIV (PWH) despite advancements in antiretroviral therapy (ART). The pathogenesis of HIV-associated NCI is linked to chronic neuroinflammation caused by HIV, even in those with successful viral suppression. Growth Differentiation Factor 15 (GDF15), a protein involved in inflammatory and metabolic stress responses, has emerged as a key player and potential biomarker for various neurological conditions. This study investigates the relationship between GDF15 expression and HIV-associated NCI. Methods: PWH from the California NeuroAIDS Tissue Network (CNTN) underwent comprehensive neuropsychological exams within 12 months before death and were categorized based on cognitive performance. We examined GDF15 levels in their CSF (Cerebrospinal Fluid) and brain tissues using immunoblotting, immunohistochemistry, double immunolabeling, and ELISA. Results: The cohort was of a similar age across HIV-associated NCI statuses (mean = 40.5), with a predominance of males (77%). The mean plasma viral load was 3.56 log₁₀ copies/mL for Neurocognitively Unimpaired (NUI) PWH and 5.38 log10 copies/mL for people with HIV-associated NCI. GDF15 protein levels were significantly elevated in the frontal cortices of PWH with NCI compared to NUI PWH. Conclusions: The findings indicate that GDF15 may play a role in the pathogenesis of HIV-associated NCI, possibly through neuroinflammatory mechanisms. The strong association between GDF15 levels and cognitive impairment severity suggests its potential as a biomarker for the early detection and monitoring of NCI in PWH.

(1) Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neu-roinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. (2) Methods: EcoHIV-infected wildtype (WT) and TREM2R47H mutant mice were used to study HIV's impact on TREM2 and behavior. TREM2 and related gene expressions were examined in mono-cyte-derived macrophages (MDMs) from PWH (n=42) and people without HIV (PWoH; n=19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. (3) Results: EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2R47H mice, with increased IBA1 protein in TREM2R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially re-versed by CBD. (4) Conclusions: These findings suggest HIV affects TREM2 expression modu-lated by cannabis and CBD, offering insights for therapeutic strategies.