Neurone-satellite glial cell interactions in dorsal root ganglia drive peripheral sensitisation in a mouse burn pain model.

Abstract

Accumulating evidence suggests that glial mechanisms are pivotal in regulating chronic pain. Our previous findings revealed that the interactions between spinal microglia and astrocytes are crucial for burn-induced pain hypersensitivity. However, the mechanisms underlying burn-induced peripheral sensitisation remain incompletely understood. Sensory neurone-satellite glial cell (SGC) interactions within peripheral dorsal root ganglia were investigated using in vitro and in vivo experiments. Behavioural tests were conducted to evaluate the therapeutic potential of targeting peripheral sensitisation mechanisms for burn pain management. Burn injury upregulated calcitonin gene-related peptide (CGRP) expression in sensory neurones (1.5-fold; P=0.013) through transient receptor potential vanilloid 1 (TRPV1) channels. Pharmacological blockade of the TRPV1/CGRP signalling pathway effectively attenuated burn-induced mechanical allodynia and thermal hyperalgesia. Additionally, neurone-derived CGRP triggered SGC activation (from 6.8% pre-injury to 41.6% at day 5 post-injury), concomitant with enhanced gap junction-mediated SGC coupling (from 16.7% pre-injury to 40.5% at day 5 post-injury). Furthermore, chemokine expression (particularly CXCL1) in SGCs was elevated after burn injury, which potentiated sensory neurone excitability and exacerbated pain hypersensitivity. Blocking SGC coupling exerted potent analgesic effects in this burn pain model. A novel neurone-SGC interaction mechanism drives burn-induced peripheral sensitisation, providing translational implications for burn pain therapeutics.