Presynaptic Modulation of Spinal Nociceptive Transmission by Glial Cell Line-Derived Neurotrophic Factor (GDNF)

The role of glial cell line-derived neurotrophic factor (GDNF) in nociceptive pathways is still controversial, as both pronociceptive and antinociceptive actions have been reported. To elucidate this role in the mouse, we performed combined structural and functional studies in vivo and in acute spinal cord slices where C-fiber activation was mimicked by capsaicin challenge. Nociceptors and their terminals in superficial dorsal horn (SDH; laminae I-II) constitute two separate subpopulations: the peptidergic CGRP/somatostatin + cells expressing GDNF and the nonpeptidergic IB4 + neurons expressing the GFR alpha 1-RET GDNF receptor complex. Ultrastructurally the dorsal part of inner lamina II (LII(i)d) harbors a mix of glomeruli that either display GDNF/somatostatin (GIb)-IR or GFR alpha 1/IB4 labeling (GIa). LII(i)d thus represents the preferential site for ligand-receptor interactions. Functionally, endogenous GDNF released from peptidergic CGRP/somatostatin + nociceptors upon capsaicin stimulation exert a tonic inhibitory control on the glutamate excitatory drive of SDH neurons as measured after ERK1/2 phosphorylation assay. Real-time Ca2+ imaging and patch-clamp experiments with bath-applied GDNF (100 nM) confirm the presynaptic inhibition of SDH neurons after stimulation of capsaicin-sensitive, nociceptive primary afferent fibers. Accordingly, the reduction of the capsaicin-evoked [Ca2+](i) rise and of the frequency of mEPSCs in SDH neurons is specifically abolished after enzymatic ablation of GFR alpha 1. Therefore, GDNF released from peptidergic CGRP/somatostatin + nociceptors acutely depresses neuronal transmission in SDH signaling to nonpeptidergic IB4 + nociceptors at glomeruli in LII(i)d. These observations are of potential pharmacological interest as they highlight a novel modality of cross talk between nociceptors that may be relevant for discrimination of pain modalities.