A study of GDNF as a therapeutic drug for neuropathic pain

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Chronic peripheral nerve injury causes plastic changes in primary afferent neurons, including changes in neurotransmitter synthesis and aberrant synaptic formation, possibly resulting in development of neuropathic pain. Two distinct populations of small sensory neurons are dependent in their survival on nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF), respectively. Therefore, expression of these neurotrophic factors after nerve injury might be responsible for the development of neuropathic pain. If so, manipulation of the expression might become one of the therapeutic strategies for intractable neuropathic pain. To explore this possibility we firstly investigated NGF and GDNF expression in the chronic constrictive injury (CCI) model, using two-site enzyme immunoassay (EIA). After allodynia and hyperalgesia were induced in the hind paw pad of the injured side, tissues were removed and subjected to EIA.While GDNF expression was unchanged in the dorsal root ganglia (DRG) of the 4th (L4) and 5th (L5) lumbar segments, NGF expression increased in the L4 and L5 DRG.GDNF and NGF expressions were decreased in the ligature segment of the sciatic nerve in the CCI side, showing impairment of ordinary neurotrophic factor transport from the respectable tissues. These results suggest that aberrant NGF expression occurs in the DRG and that expression imbalance between NGF and GDNF might play some roles in plastic changes in the sensory neurons and resultant manifestation of persistent pain. We are now investigating whether treatment with excess amount of GDNF reduces neuropathic pain.