title: 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: Division of Neuroscience, Departments of Medicine and Oral Surgery, University of California, San Francisco, CA 94143-0440, USA.
authors: Luiz F
authors: LF
authors: Ferrari
authors: Emma
authors: E
authors: Levine
authors: Jon D
authors: JD
authors: Levine
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication; D059350:Chronic Pain / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism; D008297:Male; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D034741:RNA, Small Interfering; D043682:Receptor, Adenosine A1; D051744:Protein Kinase C-epsilon; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D015232:Dinoprostone