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bioRxiv · 10.64898/2026.04.02.716115

CGRP receptor-expressing neurons in the central amygdala contributes to injury-induced pain hypersensitivity

Singh, S.·Danko, A.·Neugebauer, B.·Chaudhry, S.·Lewter, L. A.·Fortun, W.·Lin, J.·Valdivia, S.·Wilson, T. D.·Torres-Rodriguez, J. M.·Kolber, B. J.·Carrasquillo, Y.
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Abstract

The central nucleus of amygdala (CeA) comprises diverse populations of neurons, forming a complex network responsible for regulating various behavioral responses. Among these, neurons expressing calcitonin gene-related peptide receptors (CGRPR) have emerged as key players in CGRP neuropeptide-mediated pain modulation. While previous studies emphasize CGRPs key role in synaptic plasticity and its connection with pain behavior in the CeA, the precise functional attributes and contributions of CeA-CGRPR-expressing neurons in pain processing remain elusive. This study reveals the co-localization of CGRPR-expressing neurons in the CeA with phosphorylated extracellular signal-regulated kinase (pERK), a marker indicating pain plasticity, in a neuropathic pain model. Electrophysiological assessments of these neurons in slice preparations unveiled heightened intrinsic excitability after sciatic nerve cuff implantation, contingent upon their rostro-caudal positioning within the CeA. Furthermore, our behavioral experiments using chemogenetic inhibition of CeA-CGRPR neurons demonstrated the ability to reverse nerve injury-induced hypersensitivity. Conversely, activating these neurons induced pain-related hypersensitivity even in the absence of injury. Our findings also highlight a sex-specific role of CeA-CGRPR neurons in formalin-induced spontaneous pain response. Collectively, these data reinforce the involvement of CeA-CGRPR neurons in pain processing, contributing to a better understanding of how neural circuits are affected in persistent pain conditions. Significance StatementOur study shows the role of CGRPR-expressing neurons within the CeA during pain processing. Using a cuff-implanted neuropathic mouse model, we discovered that CGRPR-expressing neurons co-localize with phosphorylated extracellular signal-regulated kinase (pERK), a hallmark of pain plasticity, in both male and female mice. Furthermore, our electrophysiological investigations reveal that posterior CeA-CGRPR neurons exhibit increased excitability following sciatic nerve cuff implantation. Importantly, we demonstrate that CeA-CGRPR neurons exert bidirectional effects on pain behavior in mice, irrespective of sex differences in nerve injury-induced pain responses while showing sex-specific spontaneous pain responses in the formalin-induced model. These findings show the role of CeA-CGRPR neurons in pain modulation, underscoring their potential significance in understanding and addressing persistent pain conditions.

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Singh, S., Danko, A., Neugebauer, B., Chaudhry, S., Lewter, L. A., Fortun, W., Lin, J., Valdivia, S., Wilson, T. D., Torres-Rodriguez, J. M., Kolber, B. J., Carrasquillo, Y.. 2026-04-06. CGRP receptor-expressing neurons in the central amygdala contributes to injury-induced pain hypersensitivity. https://doi.org/10.64898/2026.04.02.716115

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