Cyclic GMP pathway is critical for inducing long-term sensitization of nociceptive sensory neurons

Nat Neurosci. 1999 Jan;2(1):18-23. doi: 10.1038/4520.


Noxious stimulation can trigger persistent sensitization of somatosensory systems that involves memory-like mechanisms. Here we report that noxious stimulation of the mollusc Aplysia produces transcription-dependent, long-term hyperexcitability (LTH) of nociceptive sensory neurons that requires a nitric oxide (NO)-cyclic GMP-protein kinase G (PKG) pathway. Injection of cGMP induced LTH, whereas antagonists of the NO-cGMP-PKG pathway prevented pinch-induced LTH. Co-injection of calcium/cAMP-responsive-element (CRE) blocked both pinch-induced LTH and cAMP-induced LTH, but antagonists of protein kinase A (PKA) failed to block pinch-induced LTH. Thus the NO-cGMP-PKG pathway and at least one other pathway, but not the cAMP-PKA pathway, are critical for inducing LTH after brief, noxious stimulation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aplysia
  • Cyclic AMP Response Element-Binding Protein / physiology
  • Cyclic GMP / metabolism*
  • Cyclic GMP / pharmacology
  • Cyclic GMP-Dependent Protein Kinases
  • Enzyme Inhibitors / pharmacology
  • Ganglia, Invertebrate / drug effects
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nociceptors / drug effects
  • Nociceptors / physiology*
  • Pain / physiopathology
  • Physical Stimulation
  • Protein Kinases / metabolism
  • Time Factors
  • Transcription, Genetic / physiology


  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Protein Kinases
  • Cyclic GMP-Dependent Protein Kinases
  • Cyclic GMP
  • NG-Nitroarginine Methyl Ester