Transcriptional changes evoked in nociceptive sensory neurons by inflammatory injury play a substantial role in the generation of and recovery from painful hypersensitivity. Transgenic mice overexpressing nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF) in the skin possess a greatly increased number of nociceptors. Surprisingly, NGF-overexpressers display reduced hypersensitivity and recovered more rapidly in response to inflammation, suggesting a compensatory suppression of nociceptive transmission in these mice. To determine whether these transgenic mice show changes in inflammation-evoked transcriptional plasticity, we examined the expression of a panel of genes implicated in nociceptive signaling in response to injection of complete Freund's adjuvant into the hindpaw. Relative mRNA levels were quantified 1, 4 and 15 days after injection using real-time PCR. In wild type mice CFA injection elicited a reproducible pattern of altered gene expression that returned to baseline over a 2-week period. In mice overexpressing NGF or GDNF the expression patterns for several genes were substantially altered; these changes in injury-evoked patterns of gene expression suggest the existence of endogenous regulatory mechanisms that can compensate for increased nociceptive input by modulating the expression of a limited subset of genes.
At least two classes of neciceptors can be distinguished based on their growth factor requirements: glial cell-line derived neurotrophic factor (GDNF)- and nerve growth factor (NGF)-dependent primary afferent neurons. Based on numerous anatomical and biochemical differences, GDNF- and NGF-dependent neurons have been proposed to be involved in the development of different types of persistent pain. To examine this hypothesis we used two lines of transgenic mice that contained a supernormal number of either NGF- or GDNF-dependent neurons (referred to as NGF-OE and GDNF-OE mice, respectively). These mice were tested in a model of inflammatory pain (induced by injection of complete Freund's adjuvant) and neuropathic pain (using a spinal nerve ligation protocol). Contrary to expectations, neither line of transgenic mice became more hyperalgesic following induction of persistent pain. In fact, NGF-OE mice recovered more rapidly and became hypoalgesic despite extensive paw swelling in the inflammatory pain model. In the neuropathic pain model, only wildtype mice became hyperalgesic. Real-time PCR analysis showed that the NGF-OE and GDNF-OE mice exhibited changes in neuronal-specific mRNAs in the dorsal root ganglia but not the spinal cord dorsal horn. These results indicate that increasing the number of nociceptors results in potent compensatory mechanisms that may begin with changes in the sensory neurons themselves.
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