Ca²⁺-Permeable AMPA Receptors Contribute to Changed Dorsal Horn Neuronal Firing and Inflammatory Pain

The dorsal horn (DH) neurons of the spinal cord play a critical role in nociceptive input integration and processing in the central nervous system. Engaged neuronal classes and cell-specific excitability shape nociceptive computation within the DH. The DH hyperexcitability (central sensitisation) has been considered a fundamental mechanism in mediating nociceptive hypersensitivity, with the proven role of Ca²⁺-permeable AMPA receptors (AMPARs). However, whether and how the DH hyperexcitability relates to changes in action potential (AP) parameters in DH neurons and if Ca²⁺-permeable AMPARs contribute to these changes remain unknown. We examined the cell-class heterogeneity of APs generated by DH neurons in inflammatory pain conditions to address these. Inflammatory-induced peripheral hypersensitivity increased DH neuronal excitability. We found changes in the AP threshold and amplitude but not kinetics (spike waveform) in DH neurons generating sustained or initial bursts of firing patterns. In contrast, there were no changes in AP parameters in the DH neurons displaying a single spike firing pattern. Genetic knockdown of the molecular mechanism responsible for the upregulation of Ca²⁺-permeable AMPARs allowed the recovery of cell-specific AP changes in peripheral inflammation. Selective inhibition of Ca²⁺-permeable AMPARs in the spinal cord alleviated nociceptive hypersensitivity, both thermal and mechanical modalities, in animals with peripheral inflammation. Thus, Ca²⁺-permeable AMPARs contribute to shaping APs in DH neurons and nociceptive hypersensitivity. This may represent a neuropathological mechanism in the DH circuits, leading to aberrant signal transfer to other nociceptive pathways.