Chronic hyperalgesic priming in the rat involves a novel interaction between cAMP and PKCepsilon second messenger pathways

Pain. 2005 Jan;113(1-2):185-90. doi: 10.1016/j.pain.2004.10.021.


Toward the goal of defining new pharmacological targets for the treatment of chronic pain conditions, in previous studies we established a model, termed 'hyperalgesic priming,' in which an acute inflammatory stimulus causes a long-lasting latent susceptibility to hyperalgesia induced by subsequent exposures to the inflammatory mediator, prostaglandin E2 (PGE2). Those investigations suggested the hypothesis that priming induces a novel linkage between the PGE2-activated second messenger cascade and the epsilon isoform of protein kinase C (PKCepsilon). In the present study, comparison of dose-response relations for hyperalgesia produced by PGE2, forskolin, 8-Br-cAMP, or the protein kinase A (PKA) catalytic subunit, in primed versus normal animals, demonstrated that priming-induced enhancement of the PGE2-activated second messenger cascade occurs downstream to adenylate cyclase and upstream to PKA. Therefore, PGE2-induced hyperalgesia in the primed animal is enhanced by the recruitment of a novel cAMP/PKCepsilon signaling pathway in addition to the usual cAMP/PKA pathway. These observations suggest that pharmacological disruption of the novel interaction between cAMP and PKCepsilon might provide a route toward the development of highly specific methods to reverse cellular processes that underlie chronic pain states.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / toxicity
  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects
  • Carrageenan
  • Colforsin / toxicity
  • Cyclic AMP / antagonists & inhibitors
  • Cyclic AMP / metabolism*
  • Cyclic AMP / physiology
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / toxicity
  • Dinoprostone / toxicity
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Hyperalgesia / chemically induced
  • Hyperalgesia / metabolism*
  • Hyperalgesia / physiopathology
  • Male
  • Models, Biological
  • Pain Measurement / methods
  • Pain Threshold / drug effects
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Protein Kinase C / physiology
  • Protein Kinase C-epsilon
  • Rats
  • Rats, Sprague-Dawley
  • Second Messenger Systems / physiology*
  • Thionucleotides / toxicity


  • Enzyme Inhibitors
  • Thionucleotides
  • 8-bromoguanosino-3',5'-cyclic monophosphorothioate
  • Colforsin
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Carrageenan
  • Cyclic AMP
  • Prkce protein, rat
  • Protein Kinase C
  • Protein Kinase C-epsilon
  • Cyclic GMP
  • Dinoprostone