Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain.

Background: Glial-derived neurotrophic factor (GDNF) and its family of ligands (GFLs) have several functions in the nervous system. As a survival factor for dopaminergic neurons, GDNF was used in clinical trials for Parkinson's disease. GFLs and their receptors are also potential targets for new pain-controlling drugs. Although molecules with analgesic activities in rodents mostly failed to be effective in translational studies, this potential should not be underestimated.

Methods: The circuitry, molecular, and cellular mechanisms by which GFLs control nociception and their intervention in inflammatory and neuropathic pain are considered first. The problems related to effective GDNF delivery to the brain and the possibility to target the GFL receptor complex rather than its ligands are then discussed, also considering the use of non-peptidyl agonists.

Conclusions: In nociceptive pathways, an ideal drug should either: i) target the release of endogenous GFLs from large dense-cored vesicles (LGVs) by acting, for example, onto the phosphatidylinositol-3-phosphate [PtdIns(3)P] pool, which is sensitive to Ca(2+) modulation, or ii) target the GFL receptor complex. Besides XIB403, a tiol molecule that enhances GFRα family receptor signaling, existing drugs such as retinoic acid and amitriptyline should be considered for effective targeting of GDNF, at least in neuropathic pain. The approach of pain modeling in experimental animals is discussed.