Heterogeneity of synaptic NMDA receptor responses within individual lamina I pain processing neurons across sex in rats and humans

Abstract

Excitatory glutamatergic NMDA receptors (NMDARs) are key regulators of spinal pain processing, and yet the biophysical properties of NMDARs in dorsal horn nociceptive neurons remain poorly understood. Despite the clinical implications, it is unknown whether the molecular and functional properties of NMDAR synaptic responses are conserved between males and females as well as from rodents to humans. To address these translational gaps, we systematically compared individual and averaged excitatory synaptic responses from lamina I pain-processing neurons of adult Sprague Dawley rats and human organ donors, including both sexes. By combining patch-clamp recordings of outward miniature excitatory postsynaptic currents with non-biased data analyses, we uncovered a wide range of decay constants of excitatory synaptic events within individual lamina I neurons. Decay constants of quantal synaptic responses were distributed in a continuum from 1-20 ms to greater than 1000 ms, suggesting that individual lamina I neurons contain AMPA receptor (AMPAR)-only as well as GluN2A-, GluN2B-, and GluN2D-NMDAR-dominated synaptic events. This intraneuronal heterogeneity in AMPAR- and NMDAR-mediated decay kinetics was observed across sex and species. However, we discovered a decreased relative contribution of GluN2B-dominated NMDAR responses as well as larger amplitude GluN2D-like events at human lamina I synapses compared to rodent synapses, suggesting species differences relevant to NMDAR subunit-targeting therapeutic approaches. The conserved heterogeneity in decay rates of excitatory synaptic events within individual lamina I pain-processing neurons may enable synapse-specific forms of plasticity and sensory integration within dorsal horn nociceptive networks.