Role of a novel nociceptor autocrine mechanism in chronic pain. Issue 10 (4th February 2013)

• Record Type: Journal Article
• Authors: Ferrari, Luiz F.; Levine, Emma; Levine, Jon D.
• Is Part Of: European journal of neuroscience. Volume 37:Issue 10(2013:May)
• Page Start: 1705
• Page End: 1713
• Publication Date: 2013-02-04
• Subjects: cAMP -- Gi protein -- hyperalgesia -- protein kinase C epsilon -- rat; Nervous system -- Periodicals; 612.8
• DOI: 10.1111/ejn.12145
• Languages: English
• ISSNs: 0953-816X

Abstract

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. Abstract : Intradermal injection of PGE2 induces a PKA‐dependent short‐term hyperalgesia. However, in a model of chronic pain, hyperalgesic priming, produced by a previous inflammatory stimulus, PGE2 hyperalgesia is prolonged; in addition to PKA, there is now a late, PKCε‐dependent, component. We provide evidence that the extracellular cAMP‐adenosine pathway, in the peripheral terminal of the nociceptor, is the underlying mechanism for the delayed PKCε‐dependent hyperalgesia.