Role of a novel nociceptor autocrine mechanism in chronic pain.

Abstract

We have previously shown, in the rat, that neuropathic and inflammatory events produce a neuroplastic change in nociceptor function whereby a subsequent exposure to a proinflammatory mediator (e.g. prostaglandin E2 ; PGE2 ) produces markedly prolonged mechanical hyperalgesia. While the initial approximately 30 min of this prolonged PGE2 hyperalgesia remains PKA-dependent, it subsequently switches to become dependent on protein kinase C epsilon (PKCε). In this study we tested the hypothesis that the delayed onset, PKCε-mediated, component of PGE2 hyperalgesia is generated by the active release of a nucleotide from the peripheral terminal of the primed nociceptor and this nucleotide is then metabolized to produce adenosine, which acts on a Gi-coupled A1 adenosine receptor on the nociceptor to generate PKCε-dependent hyperalgesia. We report that inhibitors of ATP-binding cassette transporters, of ecto-5'-phosphodiesterase and ecto-5'nucleotidase (enzymes involved in the metabolism of cyclic nucleotides to adenosine) and of A1 adenosine receptors each eliminated the late, but not the early, phase of PGE2 -induced hyperalgesia in primed animals. A second model of chronic pain induced by transient attenuation of G-protein-coupled receptor kinase 2, in which the prolongation of PGE2 hyperalgesia is not PKCε-dependent, was not attenuated by inhibitors of any of these mechanisms. Based on these results we propose a contribution of an autocrine mechanism, in the peripheral terminal of the nociceptor, in the hyperalgesic priming model of chronic pain.

• Authors: Luiz F Ferrari, Emma Levine, Jon D Levine
• Journal: The European journal of neuroscience (Eur J Neurosci) Vol. 37 Issue 10 Pg. 1705-13 (May 2013) ISSN: 1460-9568 [Electronic] France
• PMID: 23379641 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Chemical References

• Adenosine A2 Receptor Antagonists
• RNA, Small Interfering
• Receptor, Adenosine A1
• Protein Kinase C-epsilon
• Grk2 protein, rat
• G-Protein-Coupled Receptor Kinase 2
• Dinoprostone

Topics

• Adenosine A2 Receptor Antagonists (pharmacology)
• Animals
• Autocrine Communication
• Chronic Pain (metabolism)
• Dinoprostone (metabolism)
• G-Protein-Coupled Receptor Kinase 2 (genetics, metabolism)
• Hyperalgesia (metabolism)
• Male
• Nociceptors (drug effects, metabolism)
• Protein Kinase C-epsilon (metabolism)
• RNA, Small Interfering
• Rats
• Rats, Sprague-Dawley
• Receptor, Adenosine A1 (metabolism)