<p>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 (PVT^Glu) nucleus are involved in obesity-related pain. Inhibition of PVT^Glu 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 PVT^Glu neurons and induced pain hypersensitivity in control mice. In addition, increased expression of the CXC chemokine receptor 2 (CXCR2) receptor was observed in PVT^Glu neurons of obese mice. Knockdown of CXCR2 receptors in the PVT^Glu neurons attenuated PVT^Glu neuronal excitability and relieved pain hypersensitivity in obese mice. Furthermore, PVT^Glu neurons send excitatory inputs to glutamatergic neurons in the basolateral amygdala (BLA^Glu) that are required for obesity-related pain. Our study demonstrates that downregulation of CXCR2 receptors in the PVT^Glu neurons abrogated the rise in BLA^Glu neuronal activity while alleviating pain hypersensitivity in obese mice. Collectively, these findings emphasize the critical involvement of the CXCL7-CXCR2 axis enhances PVT^Glu → BLA^Glu pathway in obesity-related pain hypersensitivity, providing novel insights for the development of therapeutic strategies targeting obesity-related pain.</p>