NERVE GROWTH FACTOR AND PAIN

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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.