It is widely known that cannabinoid type 2 (CB2) receptor deficiency enhances neuroinflammation and pain development in the animal model of nerve injury-evoked neuropathic pain. We previously proposed the upregulated leptin signaling at the peripheral nerve as one of the underlying molecular mechanism, as nerve-injured CB2 receptor knockouts (CB2-KO) displayed robust upregulation of leptin receptors in both injured and non-injured nerve tissue. Those leptin receptors seemed to be expressed on the macrophages which is recruited to the nerve by the tissue injury, indicating the infiltration of leptin receptor-expressing macrophages. Thus, Due to these past results we also hypothesized that lack of CB2 receptor might also enhance the high fat diet (HFD)-induced peripheral neuroinflammation. However, surprisingly, CB2-KOs showed the significant resistance to the HFD-induced neuroinflammation. Namely, 5-week feeding of HFD induced substantial hypersensitivity in WT mice, while tactile sensitivity of HFD-fed CB2-KO remained intact. In the same animals, we further found the significant upregulation of infiltrated macrophages and chemokine receptor CXCR4 expression in HFD-fed WT animals, but not in either HFD-fed CB2 knockout mice or standard fat diet (SFD)-fed WT and CB2-KO controls. Based on these results, we will propose that CB2 receptors might have the bipolar regulatory role to chemokine receptor-mediated inflammatory response, which in the end enhance or inhibit the development of neuroinflammation depending on its cause.