The Effects of NGF and Sensory Nerve Stimulation on Collateral Sprouting and Gene Expression in Adult Sensory Neurons

Abstract

Collateral sprouting of mature cutaneous nociceptive fibers is regulated by the availability of NGF, and the onset of this sprouting can be accelerated by electrical stimulation of the intact nerve. To investigate this influence of stimulation on NGF-induced sprouting, the thoracic dorsal cutaneous nerves of adult rats were exposed and those on the left side of the animals were electrically stimulated. NGF was then administered daily for 1–12 days. At 12 days poststimulation, the extent of nociceptive fibers sprouting was examined by an established behavioral mapping technique and was found to have occurred only in the NGF-treated animals. The dorsal root ganglia (DRGs) were sampled at various times throughout the experiment and processed forin situhybridization to examine mRNA expression of the NGF receptors (p75 and trkA) and GAP-43. As well, expression of mRNAs for the neurotrophins NGF, BDNF, and NT-3 was examined. p75, trkA, and GAP-43 mRNAs were upregulated in DRGs from the NGF-treated, but not the control animals. The combination of stimulation plus NGF resulted in these increases being slightly higher than those in the absence of stimulation; however, stimulation alone had little effect on the mRNA expression. Examination of the neurotrophin mRNAs confirmed the absence of neuronal NGF and NT-3 expression and the presence of neuronal BDNF mRNA. The NGF treatment resulted in the upregulation of BDNF mRNA to peak levels within the first 2 days of treatment, although the electrical stimulation had little additional effect. These results demonstrate that exogenously supplied NGF itself can elicit sprouting from intact cutaneous nociceptive afferents and that electrical stimulation further influences the expression of mRNAs involved in the sprouting response. While the increases in NGF receptors and GAP-43 mRNA have been shown to be associated with collateral sprouting, the role of BDNF is not clear, but may be involved in altered sensory processing (i.e., hyperalgesia) that has been shown to occur subsequent to NGF administration.