Nerve Growth Factor and Pain

Abstract

Neurotrophic factors and their cognate receptors regulate the development of the nervous system of vertebrates. During the embryonic period, most primary nociceptive neurons die in the absence of an adequate supply of one target-derived trophic factor, nerve growth factor (NGF) or its receptor tropomyosin receptor kinase A (TrkA). Adult primary sensory neurons continue to be sensitive to several neurotrophic factors; about one half of primary nociceptive neurons express receptors for NGF and the other half of them express receptors for another neurotrophic factor, glial-derived neurotrophic factor (GDNF). Both NGF and GDNF control the expression of various receptors and neurotransmitters in primary nociceptive neurons. The altered availability of these factors in cases of nerve or tissue injury is a key cause of altered properties of primary nociceptive neurons.
There is increasing evidence that NGF plays a role in the hyperalgesia associated with inflammation. An increase in the tissue level of NGF occurs within hours of the initiation of inflammation. A single dose of NGF produces prolonged thermal and mechanical hyperalgesia. The thermal hyperalgesia results, in part, from sensitization of nociceptors, while mechanical hyperalgesia involves central changes. In addition to the direct actions on nociceptors, NGF induces hyperalgesia by indirect mechanisms; for instance, NGF causes mast cell degranulation that leads to the release of mediators such as serotonin and histamine.
NGF locally produced by inflammation is retrogradely transported, and triggers the upregulation of tetrodotoxin-resistant Na channels (TTXr) in the cell body of nociceptive primary sensory neurons within the dorsal root ganglion. In contrast, an axonal injury results in the downregulation of TTXr and the upregulation of a previously unexpressed, tetrodotoxin-sensitive Na channel subtype, TTXs αIII. Thus, the membrane of nociceptive primary sensory neurons is retuned, and there are changes in its electrogenic properties which can poise it to fire inappropriately. The changes in the expression of Na channels can be reversed by peripherally applied NGF.
A third neurotrophic factor, brain-derived neurotrophic factor (BDNF) is made by primary nociceptive neurons expressing TrkA. NGF transported to the cell body upregulates BDNF synthesis. BDNF is transported to central terminals in dense core vesicles and released from central terminals. BDNF in turn phosphorylates the NMDA receptor, and thus modulates the excitability of secondary nociceptive neurons within the spinal cord.