Nerve growth factor and nociception

doi:10.1016/0166-2236(93)90092-Z

Trends in Neurosciences

Volume 16, Issue 9, September 1993, Pages 353-359

https://doi.org/10.1016/0166-2236(93)90092-Z Get rights and content

Abstract

Nerve growth factor (NGF) is thought of as a target-derived factor responsible for the survival and maintaining the phenotype of specific sets of peripheral and central neurons during development and maturation. Recently, using physiological techniques, we have shown that specific functional types of nociceptive sensory neurons require NGF, first for survival during development in utero and then for their normal phenotypic development (but not survival) in the early postnatal period. In adulthood, the physiological role of NGF changes dramatically and here it may serve as a link between inflammation and hyperalgesia. Despite apparent changes in NGF's mode of action as the animal matures, it always interacts specifically with nociceptive sensory neurons.

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M. leprae infection is associated with sustained Schwann cell proliferation and distal limb nerve fiber loss. Rates of epidermal reinnervation were highest 3mo after infection and normalized by 12 mo of infection. We postulate that excess Schwann cell proliferation is the main pathogenic process and is deleterious to sensory axons. There is a compensatory initial increase in regeneration rates that may be an attempt to compensate for the injury, but it is not sustained and eventually followed by axon loss. Aberrant Schwann cell proliferation may be a novel therapeutic target to interrupt the pathogenic cascade of M. leprae.
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Citation Excerpt :
These TRK genes included the Erbb3 gene which was exclusive to enteric neurons, where it plays a critical role in development (Espinosa-Medina et al., 2017), and the Ntrk1 gene that was specific for sympathetic and sensory neuron clusters. The latter was expected given its genetic link to nociceptor and sympathetic neuron development (Lewin and Mendell, 1993; Lewin et al., 2014). There was not a difference in diversity of TRK expression between CNS and PNS neurons (Fig. 3C) although we did note a decrease in diversity in nociceptors versus all other PNS neuron types (Fig. 3D).
Because somatosensory PNS neurons, in particular nociceptors, are specially tuned to be able to detect a wide variety of both exogenous and endogenous signals, one might assume that these neurons express a greater variety of receptor genes. This assumption has not been formally tested. Because cells detect such signals via cell surface receptors, we sought to formally test the hypothesis that PNS neurons might express a broader array of cell surface receptors than CNS neurons using existing single cell RNA sequencing resources from mouse. We focused our analysis on ion channels, G-protein coupled receptors (GPCRS), receptor tyrosine kinase and cytokine family receptors. In partial support of our hypothesis, we found that mouse PNS somatosensory, sympathetic and enteric neurons and CNS neurons have similar receptor expression diversity in families of receptors examined, with the exception of GPCRs and cytokine receptors which showed greater diversity in the PNS. Surprisingly, these differences were mostly driven by enteric and sympathetic neurons, not by somatosensory neurons or nociceptors. Secondary analysis revealed many receptors that are very specifically expressed in subsets of PNS neurons, including some that are unique among neurons for nociceptors. Finally, we sought to examine specific ligand-receptor interactions between T cells and PNS and CNS neurons. Again, we noted that most interactions between these cells are shared by CNS and PNS neurons despite the fact that T cells only enter the CNS under rare circumstances. Our findings demonstrate that both PNS and CNS neurons express an astonishing array of cell surface receptors and suggest that most neurons are tuned to receive signals from other cells types, in particular immune cells.
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The R100W mutation in nerve growth factor is associated with hereditary sensory autonomic neuropathy V in a Swedish family. These patients develop severe loss of perception to deep pain but with apparently normal cognitive functions. To better understand the disease mechanism, we examined a knockin mouse model of HSAN V. The homozygous mice showed significant structural deficits in intra-epidermal nerve fibers (IENFs) at birth. These mice had a total loss of pain perception at ∼2 months of age and often failed to survive to adulthood. Heterozygous mutant mice developed a progressive degeneration of small sensory fibers both behaviorally and functionally: they showed a progressive loss of IENFs starting at the age of 9 months accompanied with progressive loss of perception to painful stimuli such as noxious temperature. Quantitative analysis of lumbar 4/5 dorsal root ganglia revealed a significant reduction in small size neurons, while analysis of sciatic nerve fibers revealed the heterozygous mutant mice had no reduction in myelinated nerve fibers. Significantly, the amount of NGF secreted from mouse embryonic fibroblasts were reduced from both heterozygous and homozygous mice compared to their wild-type littermates. Interestingly, the heterozygous mice showed no apparent structural alteration in the brain: neither the anterior cingulate cortex nor the medial septum including NGF-dependent basal forebrain cholinergic neurons. Accordingly, these animals did not develop appreciable deficits in tests for brain function. Our study has thus demonstrated that the NGF^R100W mutation likely affects the structure and function of peripheral sensory neurons.
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There are many neurotrophic factors, of which Nerve growth factor (NGF, NT1), brain-derived neurotrophic factor (BDNF, NT2), and the glial cell line-derived neurotrophic factor (GDNF) family (GDNF, neurturin, and artemin) play important roles in many forms of pain. Here, we review the involvement of these factors in inflammatory pain, neuropathic pain induced by nerve injury, bone cancer pain, musculoskeletal pain such as joint pain caused by osteoarthritis (OA), chronic low back pain (CLBP), and delayed-onset muscle soreness, and other painful conditions along with possible mechanisms of action. The prospect of treating OA and CLBP with anti-NGF antibodies is also introduced.
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Nerve Growth Factor (NGF) is a therapeutic candidate for Alzheimer’s disease, based on its well known actions on basal forebrain cholinergic neurons. However, because of its pro-nociceptive activity, in current clinical trials NGF has to be administered intraparenchymally into the brain by neurosurgery via cell or gene therapy approaches. To prevent the NGF pain-inducing collateral effects, thus avoiding the necessity for local brain injection, we developed painless NGF (hNGFp), based on the human genetic disease Hereditary Sensory and Autonomic Neuropathy type V (HSAN V). hNGFp has similar neurotrophic activity as wild type human NGF, but its pain sensitizing activity is tenfold lower. Pharmacologically, hNGFp is a biased receptor agonist of NGF TrkA receptor. The results of recent studies shed new light on the neuroprotective mechanism by hNGFp and are highly relevant for the planning of NGF-based clinical trials. The intraparenchymal delivery of hNGFp, as used in clinical trials, was simulated in the 5xFAD mouse model and found to be inefficacious in reducing Aβ plaque load. On the contrary, the same dose of hNGFp administered intranasally, which was rather widely biodistributed in the brain and did not induce pain sensitization, blocked APP processing into amyloid and restored synaptic plasticity and memory in this aggressive neurodegeneration model. This potent and broad neuroprotection by hNGFp was found to be mediated by hNGFp actions on glial cells. hNGFp increases inflammatory proteins such as the soluble TNFα receptor II and the chemokine CXCL12. Independent work has shown that NGF has a potent anti-inflammatory action on microglia and steers them towards a neuroprotective phenotype. These studies demonstrate that microglia cells are a new target cell of NGF in the brain and have therapeutic significance: i) they establish that the neuroprotective actions of hNGFp relies on a widespread exposure of the brain, ii) they identify a new anti-neurodegenerative pathway, linking hNGFp to inflammatory chemokines and cytokines via microglia, a common target for new therapeutic opportunities for neurodegenerative diseases, iii) they extend the neuroprotective potential of hNGFp beyond its classical cholinergic target, thereby widening the range of neurological diseases for which this neurotrophic factor might be used therapeutically, iv) they help interpreting the results of current NGF clinical trials in AD and the design of future trials with this new potent therapeutic candidate.
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Trends in Neurosciences

Abstract

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Cited by (476)

Mycobacterium leprae induces Schwann cell proliferation and migration in a denervated milieu following intracutaneous excision axotomy in nine-banded armadillos

Diversity of Receptor Expression in Central and Peripheral Mouse Neurons Estimated from Single Cell RNA Sequencing

A missense point mutation in nerve growth factor (NGF<sup>R100W</sup>) results in selective peripheral sensory neuropathy

5.10 - Neurotrophins and Pain

Painless Nerve Growth Factor: A TrkA biased agonist mediating a broad neuroprotection via its actions on microglia cells

Terpenes in Cannabis sativa Inhibit Capsaicin Responses in Rat DRG Neurons via Na<sup>+</sup>/K<sup>+</sup> ATPase Activation

Trends in Neurosciences

ReviewNerve growth factor and nociception

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Review
Nerve growth factor and nociception