CXCL7/CXCR2 in the paraventricular thalamus mediates obesity-related pain.

High-fat diets represent a primary factor driving the global obesity epidemic, thereby constituting a substantial public health challenge. Previous research has demonstrated that obese individuals exhibiting a higher prevalence of pain-related disorders. However, the underlying neural mechanisms involved remain largely unknown. Here, we identified that glutamatergic neurons in the paraventricular thalamus (PVTGlu) nucleus are involved in obesity-related pain. Inhibition of PVTGlu neurons reversed the pain hypersensitivity in obese mice. Proteomic analysis of plasma samples from obese patients revealed a marked increase in the level of the chemokine (C-X-C motif) ligand 7 (CXCL7). Infusion of CXCL7 into the PVT increased the excitability of PVTGlu neurons and induced pain hypersensitivity in control mice. In addition, increased expression of the CXC chemokine receptor 2 (CXCR2) receptor was observed in PVTGlu neurons of obese mice. Knockdown of CXCR2 receptors in the PVTGlu neurons attenuated PVTGlu neuronal excitability and relieved pain hypersensitivity in obese mice. Furthermore, PVTGlu neurons send excitatory inputs to glutamatergic neurons in the basolateral amygdala (BLAGlu) that are required for obesity-related pain. Our study demonstrates that downregulation of CXCR2 receptors in the PVTGlu neurons abrogated the rise in BLAGlu neuronal activity while alleviating pain hypersensitivity in obese mice. Collectively, these findings emphasize the critical involvement of the CXCL7-CXCR2 axis enhances PVTGlu → BLAGlu pathway in obesity-related pain hypersensitivity, providing novel insights for the development of therapeutic strategies targeting obesity-related pain.