Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurons

Abstract

Nerve growth factor (NGF) is a trophic molecule essential for the survival of sympathetic and sensory neurons during ontogeny. The extent to which NGF is involved in the maintenance or regulation of the differentiated phenotypes of mature peripheral neurons is much less clear, however. Biochemical analysis of the actions of NGF upon peripheral neurons has been hampered by the lack of a preparation of neuronal cells that are responsive to NGF but do not require it for survival. We report here that in adult dorsal root ganglion neurons, which can be isolated, enriched and maintained in culture in the absence of neuronal growth factors, the expression of mRNAs encoding the precursors of two neuropeptides, substance P and calcitonin gene-related peptide is regulated by NGF. Our results provide the first direct evidence of a continuous dynamic role for NGF in regulation of peptide neurotransmitter/neuromodulator levels in mature sensory neurons.

The expanding role of nerve growth factor: from neurotrophic activity to immunologic diseases

“…These biologic activities are tuediated by the NGF binding to two receptors: TrkA (a tyrosine kinase receptor) and p75 (a low-affinity receptor which can also bind the other neurotrophins) (31-33). In the peripheral nervous system during postnatal and adult life, one key effect of NGF is to stimulate axon regeneration of injured nerve cells and to enhance the synthesis and release of neurotransmitters and neuropeptides, such as substance P (SP) and calcitonin gene-related peptide in peripheral neurons (34,35).…”

Contribution of interleukin‐1β to the inflammation‐induced increase in nerve growth factor levels and inflammatory hyperalgesia

“…The precise molecular events responsible for the sensory changes at the site of the inflammation and surrounding tissue are not yet fully understood, but changes both in the transduction sensitivity of the high threshold nociceptors and in excitability in the central nervous system secondary to the activation of chemosensitive IL-13, NGF and hyperalgesia and changes in transcription factor expression, it controls the survival, growth and phenotype of immature neurones (Rich et al, 1987;Matsuda et al, 1988;Barde, 1989;Chao, 1992;Glass & Yancopoulos, 1993). In addition to this specific neurotrophic action during development, a constant supply of NGF from the periphery may be important for the maintenance of normal phenotype in trkA receptor expressing nociceptive adult primary sensory neurones (Lindsay & Harmar, 1989). Removal of NGF results in a down regulation of several transmitters and proteins (Rich et al, 1984;Gold et al, 1991) while an excess results in abnormal sensitivity .…”

“…The indirect effects of NGF may result from its cytokine-like actions, including stimulation of growth and differentiation of human B lymphocytes Thorpe et al, 1988;Treede et al, 1992), the release of inflammatory mediators from lymphocytes and basophils (Bischoff & Dahinden, 1992;Horigome et al, 1993) and a degranulation of mast cells (Aloe & Levi-Montalcini, 1977;Bohm et al, 1986;Mazurek et al, 1986;Pearce & Thompson, 1986). Direct effects could either be due to a trkA receptor-tyrosine kinase-mediated phosphorylation at the nociceptor terminal, increasing transduction sensitivity, or a consequence of a change in the expression of transmitter/neuromodulators such as substance P and calcitonin gene-related peptide (CGRP) in the cell body (Lindsay & Harmar, 1989;Woolf et al, 1994), amplifying the central actions of the nociceptor in the spinal cord (Lewin et al, 1994).…”

Subpoblaciones neuronales presentes en el ganglio de la raíz dorsal

“…In vitro, por el contrario, el número de neuronas positivas para SP y otros neuropéptidos, como el péptido relacionado con el gen de la calcitonina (CGRP), disminuye (28 y 37%, respectivamente) por la ausencia de factores tróficos, como el factor de crecimiento nervioso (NGF) en el medio de cultivo, que in vivo son suministrados por el blanco periférico, pero que no están presentes en el cultivo y cuya función en parte es mantener el fenotipo neuronal (24)(25)(26). Adicionalmente, se ha visto que, en cultivo de ratón neonatal, si se adiciona al medio NGF, el porcentaje de inmunorreactividad (IR) para SP vuelve a sus niveles normales (8).…”

“…Entre 10 y 20% de la población neuronal total es positiva para este péptido en el GRD (16,24). En cultivo se presenta una disminución ( < l o % ) y, a pesar de la administración de NGF, los niveles de somatostatina (SOM) no vuelven a sus porcentajes normales, contrario a lo que pasa con SP y GGRP (25).…”