​​​​PRESYNAPTIC INHIBITION OF C- AND ADELTA-FIBRE INPUTS TO SUPERFICIAL DORSAL HORN NEURONS

Primary afferents transmit nociceptive information to superficial dorsal neurons, which constitute the first level for nociceptive processing. Even before nociceptive information reaches second-order neurons, synaptic contacts from dorsal neurons onto primary afferent terminals adjust their excitability and neurotransmitter release. Our objective was to analyse the role of neurons expressing the gad2 enzyme (gad2-neurons) in regulating the presynaptic activity of C- and Aδ-afferents.
Whole-cell patch clamp recordings of superficial dorsal horn neurons were performed in ex vivo spinal cord preparations obtained from neonatal mice. Naïve and carrageenan-inflamed animals were used to identify changes due to central sensitisation. Primary afferents were activated using graded electrical stimuli on the dorsal root. Optogenetics was used to selectively activate gad2-neurons to study their influence on monosynaptic inputs from C- and Aδ-afferents.
Gad2-neurons showed tonic or phasic firing patterns, with a more depolarised resting potential and wider action potentials compared with no gad2-neurons. Optogenetic activation of gad2-neurons produced direct and continuous depolarisation of the primary afferents recorded from the dorsal root. Stimulation of gad2-neurons reduced the amplitude of monosynaptic inputs from Aδ-afferents (n=9), with an averaged depression to 67% of control values in the excitatory postsynaptic currents evoked by dorsal root electrical stimulation. In contrast, C-fibre inputs were mostly unaffected. No significant differences between naïve and inflammatory conditions were found.
Gad2-neurons connect directly with primary afferent terminals, causing depolarisation and a reduction in synaptic inputs from Aδ-afferents. This presynaptic inhibition mechanism maintains its function after an inflammatory process.
Funded by Ministerio Ciencia Innovación y Universidades (PID2024-158827OB-I00).