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

Chen, Q.; Wu, H.; Xie, S.; Zhu, F.; Xu, F.; Xu, Q.; Sun, L.; Yang, Y.; Xie, L.; Xie, J.; Li, H.; Dai, A.; Zhang, W.; Wang, L.; Jiao, C.; Zhang, H.; Xu, Z.-Z.; Chen, X.

doi:10.1101/2024.09.24.614834

bioRxiv · 10.1101/2024.09.24.614834

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

Chen, Q.·Wu, H.·Xie, S.·Zhu, F.·Xu, F.·Xu, Q.·Sun, L.·Yang, Y.·Xie, L.·Xie, J.·Li, H.·Dai, A.·Zhang, W.·Wang, L.·Jiao, C.·Zhang, H.·Xu, Z.-Z.·Chen, X.

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Abstract

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 show that the membrane estrogen receptor G-protein coupled estrogen receptor (GPER/GPR30) in spinal neurons was significantly upregulated in chronic constriction injury (CCI) mice and that inhibition of GPR30 in CCK+ neurons reversed CCI-induced neuropathic pain. Furthermore, GPR30 in spinal CCK+ neurons was essential for the enhancement of AMPA-mediated excitatory synaptic transmission in CCI mice. Moreover, GPR30 was expressed in spinal CCK+ neurons that received 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 was required for CCI-induced neuropathic pain. Taken together, our findings suggest that GPR30 in spinal CCK+ neurons and S1-SDH postsynaptic neurons is pivotal for neuropathic pain, thereby representing a promising therapeutic target for neuropathic pain.

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Chen, Q., Wu, H., Xie, S., Zhu, F., Xu, F., Xu, Q., Sun, L., Yang, Y., Xie, L., Xie, J., Li, H., Dai, A., Zhang, W., Wang, L., Jiao, C., Zhang, H., Xu, Z.-Z., Chen, X.. 2024-09-26. GPR30 in spinal cholecystokinin-positive neurons modulates neuropathic pain via mediating descending facilitation. https://doi.org/10.1101/2024.09.24.614834

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