Stimulus-evoked release of neuropeptides is enhanced in sensory neurons from mice with a heterozygous mutation of the Nf1 gene

C. M. Hingtgen, S. L. Roy, D. Clapp

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Neurofibromatosis type I is a common autosomal dominant disease characterized by formation of multiple benign and malignant tumors. People with this disorder also experience chronic pain, which can be disabling. Neurofibrinomin, the protein product of the NF1 gene (neurofibromin gene (human)), is a guanosine triphosphate activating protein for p21ras. Loss of NF1 results in an increase in activity of the p21ras transduction cascade. Because of the growing evidence suggesting involvement of downstream components of the p21ras transduction cascade in the sensitization of nociceptive sensory neurons, we examined the stimulus-evoked release of the neuropeptides, substance P and calcitonin gene-related peptide, from primary sensory neurons of mice with a mutation of the Nf1 gene (neurofibromin gene (mouse)) (Nf1+/-). Measuring immunoreactive substance P and immunoreactive calcitonin gene-related peptide by radioimmunoassay, we demonstrated that capsaicin-stimulated release of neuropeptides is three to five-fold higher in spinal cord slices from Nf1+/- mice than from wildtype mouse tissue. In addition, the potassium and capsaicin-stimulated release of immunoreactive calcitonin gene-related peptide from cultures of sensory neurons isolated from Nf1+/- mice was more than double that from cultures of wildtype neurons. Treatment of wildtype sensory neurons with nerve growth factor for 5-7 days mimicked the enhanced stimulus-evoked release observed from the Nf1+/- neurons. When nerve growth factor was removed 48 h before conducting release experiments, nerve growth factor-induced augmentation of immunoreactive calcitonin gene-related peptide release from Nf1+/- neurons was more pronounced than in Nf1+/- sensory neurons that were treated with nerve growth factor continuously for 5-7 days. Thus, sensory neurons from mice with a heterozygous mutation of the Nf1 gene that is analogous to the human disease neurofibromatosis type I, exhibit increased sensitivity to chemical stimulation. This augmented responsiveness may explain the abnormal pain sensations experienced by people with neurofibromatosis type I and suggests an important role for guanosine triphosphate activating proteins, in the regulation of nociceptive sensory neuron sensitization.

Original languageEnglish
Pages (from-to)637-645
Number of pages9
JournalNeuroscience
Volume137
Issue number2
DOIs
StatePublished - 2006

Fingerprint

Neurofibromatosis 1 Genes
Sensory Receptor Cells
Neuropeptides
Calcitonin Gene-Related Peptide
Mutation
Nerve Growth Factor
Neurofibromatosis 1
Neurofibromin 1
Nociceptors
Capsaicin
Substance P
Guanosine Triphosphate
Neurons
Chemical Stimulation
Proteins
Chronic Pain
Radioimmunoassay
Spinal Cord
Potassium
Pain

Keywords

  • Calcitonin gene-related peptide
  • Dorsal root ganglia
  • Nerve growth factor
  • Neurofibromatosis
  • Ras
  • Substance P

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Stimulus-evoked release of neuropeptides is enhanced in sensory neurons from mice with a heterozygous mutation of the Nf1 gene. / Hingtgen, C. M.; Roy, S. L.; Clapp, D.

In: Neuroscience, Vol. 137, No. 2, 2006, p. 637-645.

Research output: Contribution to journalArticle

@article{26a32a19fa164135a16f61fadcd03301,
title = "Stimulus-evoked release of neuropeptides is enhanced in sensory neurons from mice with a heterozygous mutation of the Nf1 gene",
abstract = "Neurofibromatosis type I is a common autosomal dominant disease characterized by formation of multiple benign and malignant tumors. People with this disorder also experience chronic pain, which can be disabling. Neurofibrinomin, the protein product of the NF1 gene (neurofibromin gene (human)), is a guanosine triphosphate activating protein for p21ras. Loss of NF1 results in an increase in activity of the p21ras transduction cascade. Because of the growing evidence suggesting involvement of downstream components of the p21ras transduction cascade in the sensitization of nociceptive sensory neurons, we examined the stimulus-evoked release of the neuropeptides, substance P and calcitonin gene-related peptide, from primary sensory neurons of mice with a mutation of the Nf1 gene (neurofibromin gene (mouse)) (Nf1+/-). Measuring immunoreactive substance P and immunoreactive calcitonin gene-related peptide by radioimmunoassay, we demonstrated that capsaicin-stimulated release of neuropeptides is three to five-fold higher in spinal cord slices from Nf1+/- mice than from wildtype mouse tissue. In addition, the potassium and capsaicin-stimulated release of immunoreactive calcitonin gene-related peptide from cultures of sensory neurons isolated from Nf1+/- mice was more than double that from cultures of wildtype neurons. Treatment of wildtype sensory neurons with nerve growth factor for 5-7 days mimicked the enhanced stimulus-evoked release observed from the Nf1+/- neurons. When nerve growth factor was removed 48 h before conducting release experiments, nerve growth factor-induced augmentation of immunoreactive calcitonin gene-related peptide release from Nf1+/- neurons was more pronounced than in Nf1+/- sensory neurons that were treated with nerve growth factor continuously for 5-7 days. Thus, sensory neurons from mice with a heterozygous mutation of the Nf1 gene that is analogous to the human disease neurofibromatosis type I, exhibit increased sensitivity to chemical stimulation. This augmented responsiveness may explain the abnormal pain sensations experienced by people with neurofibromatosis type I and suggests an important role for guanosine triphosphate activating proteins, in the regulation of nociceptive sensory neuron sensitization.",
keywords = "Calcitonin gene-related peptide, Dorsal root ganglia, Nerve growth factor, Neurofibromatosis, Ras, Substance P",
author = "Hingtgen, {C. M.} and Roy, {S. L.} and D. Clapp",
year = "2006",
doi = "10.1016/j.neuroscience.2005.09.030",
language = "English",
volume = "137",
pages = "637--645",
journal = "Neuroscience",
issn = "0306-4522",
publisher = "Elsevier Limited",
number = "2",

}

TY - JOUR

T1 - Stimulus-evoked release of neuropeptides is enhanced in sensory neurons from mice with a heterozygous mutation of the Nf1 gene

AU - Hingtgen, C. M.

AU - Roy, S. L.

AU - Clapp, D.

PY - 2006

Y1 - 2006

N2 - Neurofibromatosis type I is a common autosomal dominant disease characterized by formation of multiple benign and malignant tumors. People with this disorder also experience chronic pain, which can be disabling. Neurofibrinomin, the protein product of the NF1 gene (neurofibromin gene (human)), is a guanosine triphosphate activating protein for p21ras. Loss of NF1 results in an increase in activity of the p21ras transduction cascade. Because of the growing evidence suggesting involvement of downstream components of the p21ras transduction cascade in the sensitization of nociceptive sensory neurons, we examined the stimulus-evoked release of the neuropeptides, substance P and calcitonin gene-related peptide, from primary sensory neurons of mice with a mutation of the Nf1 gene (neurofibromin gene (mouse)) (Nf1+/-). Measuring immunoreactive substance P and immunoreactive calcitonin gene-related peptide by radioimmunoassay, we demonstrated that capsaicin-stimulated release of neuropeptides is three to five-fold higher in spinal cord slices from Nf1+/- mice than from wildtype mouse tissue. In addition, the potassium and capsaicin-stimulated release of immunoreactive calcitonin gene-related peptide from cultures of sensory neurons isolated from Nf1+/- mice was more than double that from cultures of wildtype neurons. Treatment of wildtype sensory neurons with nerve growth factor for 5-7 days mimicked the enhanced stimulus-evoked release observed from the Nf1+/- neurons. When nerve growth factor was removed 48 h before conducting release experiments, nerve growth factor-induced augmentation of immunoreactive calcitonin gene-related peptide release from Nf1+/- neurons was more pronounced than in Nf1+/- sensory neurons that were treated with nerve growth factor continuously for 5-7 days. Thus, sensory neurons from mice with a heterozygous mutation of the Nf1 gene that is analogous to the human disease neurofibromatosis type I, exhibit increased sensitivity to chemical stimulation. This augmented responsiveness may explain the abnormal pain sensations experienced by people with neurofibromatosis type I and suggests an important role for guanosine triphosphate activating proteins, in the regulation of nociceptive sensory neuron sensitization.

AB - Neurofibromatosis type I is a common autosomal dominant disease characterized by formation of multiple benign and malignant tumors. People with this disorder also experience chronic pain, which can be disabling. Neurofibrinomin, the protein product of the NF1 gene (neurofibromin gene (human)), is a guanosine triphosphate activating protein for p21ras. Loss of NF1 results in an increase in activity of the p21ras transduction cascade. Because of the growing evidence suggesting involvement of downstream components of the p21ras transduction cascade in the sensitization of nociceptive sensory neurons, we examined the stimulus-evoked release of the neuropeptides, substance P and calcitonin gene-related peptide, from primary sensory neurons of mice with a mutation of the Nf1 gene (neurofibromin gene (mouse)) (Nf1+/-). Measuring immunoreactive substance P and immunoreactive calcitonin gene-related peptide by radioimmunoassay, we demonstrated that capsaicin-stimulated release of neuropeptides is three to five-fold higher in spinal cord slices from Nf1+/- mice than from wildtype mouse tissue. In addition, the potassium and capsaicin-stimulated release of immunoreactive calcitonin gene-related peptide from cultures of sensory neurons isolated from Nf1+/- mice was more than double that from cultures of wildtype neurons. Treatment of wildtype sensory neurons with nerve growth factor for 5-7 days mimicked the enhanced stimulus-evoked release observed from the Nf1+/- neurons. When nerve growth factor was removed 48 h before conducting release experiments, nerve growth factor-induced augmentation of immunoreactive calcitonin gene-related peptide release from Nf1+/- neurons was more pronounced than in Nf1+/- sensory neurons that were treated with nerve growth factor continuously for 5-7 days. Thus, sensory neurons from mice with a heterozygous mutation of the Nf1 gene that is analogous to the human disease neurofibromatosis type I, exhibit increased sensitivity to chemical stimulation. This augmented responsiveness may explain the abnormal pain sensations experienced by people with neurofibromatosis type I and suggests an important role for guanosine triphosphate activating proteins, in the regulation of nociceptive sensory neuron sensitization.

KW - Calcitonin gene-related peptide

KW - Dorsal root ganglia

KW - Nerve growth factor

KW - Neurofibromatosis

KW - Ras

KW - Substance P

UR - http://www.scopus.com/inward/record.url?scp=29744457736&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=29744457736&partnerID=8YFLogxK

U2 - 10.1016/j.neuroscience.2005.09.030

DO - 10.1016/j.neuroscience.2005.09.030

M3 - Article

C2 - 16298082

AN - SCOPUS:29744457736

VL - 137

SP - 637

EP - 645

JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

IS - 2

ER -