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Human lesions and animal studies link the claustrum to perception, salience, sleep and pain.Brain. 2022; 145: 1610-1623https://doi.org/10.1093/brain/awac114Crossref PubMed Scopus (8) Google Scholar; however, it remains unclear whether and how the claustrum participates in nociceptive processing and high-order pain behaviors. Inhibition of ACC activity reverses mechanical allodynia in animal models of persistent and neuropathic pain,1Bliss T.V. Collingridge G.L. Kaang B.K. Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain.Nat. Rev. Neurosci. 2016; 17: 485-496https://doi.org/10.1038/nrn.2016.68Crossref PubMed Scopus (460) Google Scholar,9Kang S.J. Kwak C. Lee J. Sim S.E. Shim J. Choi T. Collingridge G.L. Zhuo M. Kaang B.K. Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC.Mol. Brain. 2015; 8: 81https://doi.org/10.1186/s13041-015-0170-6Crossref PubMed Scopus (110) Google Scholar,28LaGraize S.C. Labuda C.J. Rutledge M.A. Jackson R.L. Fuchs P.N. Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain.Exp. Neurol. 2004; 188: 139-148https://doi.org/10.1016/j.expneurol.2004.04.003Crossref PubMed Scopus (142) Google Scholar suggesting claustrum inputs may function to attenuate pain processing. In this study, we sought to define claustrum function in acute and chronic pain. We found enhanced claustrum activity after a painful stimulus that was attenuated in chronic inflammatory pain. Selective inhibition of claustrocingulate projection neurons enhanced acute nociception but blocked pain learning. Inversely, chemogenetic activation of claustrocingulate neurons had no effect on basal nociception but rescued inflammation-induced mechanical allodynia. Together, these results suggest that claustrocingulate neurons are a critical component of the pain neuromatrix, and dysregulation of this connection may contribute to chronic pain.
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