Cannabinoid CB2 receptors enhance high-fat diet evoked peripheral neuroinflammation

It is known that the cannabinoid type 2 (CB2) receptor has an anti-inflammatory role. Therefore, animals without CB2 receptors show enhanced inflammation and pain in the model of chronic pain, e.g., neuropathic pain. We previously proposed the upregulated leptin signaling at the peripheral nerve as one of the underlying molecular mechanisms of pain exacerbation in nerve-injured CB2 knockouts, as they displayed robust upregulation of leptin receptors and leptin signaling in the peripheral nerve. Due to these past results, we hypothesized that CB2 receptor deficiency might also modify the peripheral neuroinflammation led by chronic exposure to a high-fat diet (HFD). Interestingly, CB2 knockout animals showed significant resistance to HFD-induced neuroinflammation. Namely, 5-week feeding of HFD induced substantial hypersensitivity in WT animals, while tactile sensitivity of HFD-fed CB2 knockouts remained intact. HFD-fed WT animals also displayed the robust upregulation of chemokine CXCR4 expression with increased macrophage infiltration, which was never observed in HFD-fed CB2 knockout mice. Moreover, 5-week HFD exposure led significant increase of CD11b