GDNF family (GFL) and pain

Abstract

Glial cell line–derived neurotrophic factor (GDNF) family ligand (GFL) consists of GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). These GFLs signal through a receptor complex consisting of coreceptor (GFRα1–4) as a ligand binding component, which has no intracellular domain and is anchored to the plasma membrane with glycosylphosphatidylinositol, and the transmembrane RET (rearranged during transfection) receptor tyrosine kinase as a signaling component. These GFRαs define ligand specificity: GDNF binds to GFRα1, NRTN to GFRα2, ARTN to GFRα3, and PSPN to GFRα4 with high affinity. Small dorsal root ganglion (DRG) neurons have been classified with binding property to plant lectin IB4, and majority of IB4–binding DRG neurons express RET. In rats about 80% of IB4–binding nociceptive DRG neurons express either GFRα1, or GFRα2, or both.

GDNF sensitizes nociceptors to mechanical and thermal stimuli when injected into the skin, and also sensitizes muscle nociceptors to mechanical stimulus when injected to the muscle, inducing behavioral mechanical hypersensitivity. Authors’ group showed that GDNF produced by muscle cells ⁄ satellite cells plays a pivotal role in mechanical nociceptive hypersensitivity after exercise (delayed onset muscle soreness). In experimentally induced inflammation, GDNF, NRTN and ARTN, and their receptors GFRα1, 2 and 3 are involved in nociceptive hypersensitivity. In contrast to inflammatory pain, intrathecally injected GDNF induces analgesia in neuropathic painful conditions. Clinical usage of GDNF for the treatment of neuropathic pain is not feasible because of side effects such as body weight loss and allodynia.