EXPRESS: Phospholipase C gamma mediates endogenous brain-derived neurotrophic factor - regulated calcitonin gene-related peptide expression in colitis - induced visceral pain

Mol Pain. 2016 Jun 15;12:1744806916657088. doi: 10.1177/1744806916657088. Print 2016.

Abstract

Background: Visceral hypersensitivity is a complex pathophysiological paradigm with unclear mechanisms. Primary afferent neuronal plasticity marked by alterations in neuroactive compounds such as calcitonin gene-related peptide is suggested to underlie the heightened sensory responses. Signal transduction that leads to calcitonin gene-related peptide expression thereby sensory neuroplasticity during colitis remains to be elucidated.

Results: In a rat model with colitis induced by 2,4,6-trinitrobenzene sulfonic acid, we found that endogenously elevated brain-derived neurotrophic factor elicited an up-regulation of calcitonin gene-related peptide in the lumbar L1 dorsal root ganglia. At seven days of colitis, neutralization of brain-derived neurotrophic factor with a specific brain-derived neurotrophic factor antibody reversed calcitonin gene-related peptide up-regulation in the dorsal root ganglia. Colitis-induced calcitonin gene-related peptide transcription was also inhibited by brain-derived neurotrophic factor antibody treatment. Signal transduction studies with dorsal root ganglia explants showed that brain-derived neurotrophic factor-induced calcitonin generelated peptide expression was mediated by the phospholipase C gamma, but not the phosphatidylinositol 3-kinase/Akt or the mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway. Application of PLC inhibitor U73122 in vivo confirmed that colitis-induced and brain-derived neurotrophic factor-mediated calcitonin gene-related peptide up-regulation in the dorsal root ganglia was regulated by the phospholipase C gamma pathway. In contrast, suppression of the phosphatidylinositol 3-kinase activity in vivo had no effect on colitis-induced calcitonin gene-related peptide expression. During colitis, calcitonin gene-related peptide also co-expressed with phospholipase C gamma but not with p-Akt. Calcitonin gene-related peptide up-regulation during colitis correlated to the activation of cAMP-responsive element binding protein in the same neurons. Consistently, colitis-induced cAMP-responsive element binding protein activation in the dorsal root ganglia was attenuated by brain-derived neurotrophic factor antibody treatment.

Conclusion: These results suggest that colitis-induced and brain-derived neurotrophic factor-mediated calcitonin generelated peptide expression in sensory activation is regulated by a unique pathway involving brain-derived neurotrophic factorphospholipase C gamma-cAMP-responsive element binding protein axis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Calcitonin Gene-Related Peptide / metabolism*
  • Colitis / complications*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Ganglia, Spinal / metabolism
  • Lumbar Vertebrae / metabolism
  • Lumbar Vertebrae / pathology
  • Male
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phospholipase C gamma / metabolism*
  • Phosphorylation
  • Protein Transport
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Up-Regulation
  • Visceral Pain / etiology*
  • Visceral Pain / metabolism*

Substances

  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Phospholipase C gamma
  • Calcitonin Gene-Related Peptide