CGRP receptor-expressing neurons in the central amygdala contributes to injury-induced pain hypersensitivity
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.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 CGRP’s 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 Statement
Our 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.
