NERVE GROWTH FACTOR AND PAIN

尽管NGF在炎症性疼痛中的作用现在已经被广泛接受，但这种神经营养因子使外周伤害性神经元敏感的机制仍然不清楚。这个问题在一定程度上是因为皮肤中表达神经生长因子的高亲和力受体TrkA的神经性和非神经性细胞类型的多样性。NGF通过表达TrkA的肥大细胞间接影响伤害性感受器的可能性得到了一些实验支持。然而，有一些证据表明，NGF可以绕过肥大细胞，使伤害性感受器对伤害性热量敏感。我们最近用NGF急性调节分离的DRG神经元辣椒素诱发电流的初步数据表明，NGF可能对DRG神经元产生直接影响。辣椒素可以被视为有毒热量的替代品，因为后者激活了辣椒素受体VR1。因此，NGF可能直接敏化对毒热的反应。对这一作用的进一步研究建议使用膜片钳方法来检验一些假说：a)。神经营养素通过其相应的trk受体的作用直接影响伤害性感受神经元对伤害性刺激的反应；b)NGF对辣椒素和辣椒素具有相同的敏化作用，并且对小DRG细胞的胞体和多模式伤害性感受器的终末的伤害性热反应都具有相同的敏化作用；c)向发炎的皮肤或皮肤提供基因改变的神经营养素表达的细胞对急性应用神经营养素的反应不同。这些实验的完成将进一步了解NGF对伤害性热敏感的痛觉感受器的生理学和病理生理学。

Although a role for NGF in inflammatory pain is now well accepted, the mechanism by which this neurotrophin sensitizes nociceptive neurons in the periphery is still not well understood. In part this problem arises from the multiplicity of cell types, both neural and non-neural, in the skin that express trkA, the high affinity receptor for NGF. The possibility that NGF affects nociceptors indirectly via trkA-expressing mast cells has obtained some experimental support. However, there is some evidence that NGF can bypass mast cells to sensitize nociceptors to noxious heat. Our recent preliminary data using NGF to acutely condition capsaicin evoked currents in isolated DRG neurons indicate that NGF may elicit direct effects on DRG neurons. Capsaicin can be viewed as a surrogate for noxious heat since the latter activates the capsaicin receptor VR1. It therefore follows that NGF may sensitize the response to noxious heat directly. Further study of this action is proposed using patch clamp methodology to examine a number of hypotheses: a). Neurotrophins have a direct effect on the response of nociceptive neurons to nociceptive stimuli via the action of their corresponding trk receptor; b) NGF has the same sensitizing action on the capsaicin and noxious heat responses of both the somata of small DRG cells and the terminals of polymodal nociceptors; c) Cells supplying inflamed skin or skin with genetically altered levels of neurotrophin expression respond differently to acutely applied neurotrophins. Completion of these experiments will provide further understanding of the physiology and pathophysiology of the sensitization of nociceptors to noxious heat by NGF.