GPR30 in spinal cholecystokinin-positive neurons modulates neuropathic pain via mediating descending facilitation

Neuropathic pain, a major health problem affecting 7 - 10% of the global population, lacks effective treatment due to its elusive mechanisms. Cholecystokinin-positive (CCK ⁺ ) neurons in the spinal dorsal horn (SDH) are critical for neuropathic pain, yet the underlying molecular mechanisms remain unclear. Here we showed that the membrane estrogen receptor G-protein coupled estrogen receptor (GPER/GPR30) in spinal was significantly upregulated in chronic constriction injury (CCI) mice and that inhibition of GPR30 in CCK ⁺ neurons reversed CCI-induced neuropathic pain. Besides, GPR30 in spinal CCK ⁺ neurons was essential for the enhancement of AMPA-mediated excitatory synaptic transmission in CCI mice. Furthermore, GPR30 was expressed in the spinal CCK ⁺ neurons receiving direct projection from the primary sensory cortex (S1-SDH). Chemogenetic inhibition of S1-SDH post-synaptic neurons alleviated CCI-induced neuropathic pain. Conversely, chemogenetic activation of these neurons mimicked neuropathic pain symptoms, which were attenuated by spinal inhibition of GPR30. Finally, we confirmed that GPR30 in S1-SDH post-synaptic neurons is required for CCI-induced neuropathic pain. Taken together, our findings suggest that GPR30 in spinal CCK ⁺ neurons is pivotal for neuropathic pain and mediates descending facilitation by corticospinal direct projections, thereby representing a promising therapeutic target for neuropathic pain.