A study of GDNF as a therapeutic drug for neuropathic pain

慢性周围神经损伤引起初级传入神经元的可塑性改变，包括神经递质合成和异常突触形成的改变，可能导致神经病理性疼痛的发生。两类不同的小感觉神经元的生存分别依赖于神经生长因子(NGF)和胶质细胞系衍生神经营养因子(GDNF)。因此，神经损伤后这些神经营养因子的表达可能与神经病理性疼痛的发生有关。如果是这样的话，操纵表达可能成为治疗顽固性神经病理性疼痛的策略之一。为了探索这种可能性，我们首先用双部位酶免疫分析法(EIA)研究了NGF和GDNF在慢性缩窄性损伤(CCI)模型中的表达。在损伤侧后爪垫诱发痛觉异常和痛觉过敏后，取出组织行EIA。在L4和L5节段的背根节(DRG)中，GDNF的表达没有变化，而在L4和L5节段，NGF的表达增加，在CCI侧的坐骨神经结扎段，GDNF和NGF的表达减少，表明正常神经营养因子从可切除组织中的运输受到阻碍。这些结果提示，背根神经节中存在NGF的异常表达，NGF和GDNF之间的表达失衡可能在感觉神经元的可塑性改变和持续性疼痛的表现中起一定作用。我们现在正在研究过量的GDNF治疗是否可以减少神经病理性疼痛。

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.