Role of a novel nociceptor autocrine mechanism in chronic pain

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 E 2 ; PGE 2 ) produces markedly prolonged mechanical hyperalgesia. While the initial approximately 30 min of this prolonged PGE 2 hyperalgesia remains PKA ‐dependent, it subsequently switches to become dependent on protein kinase C epsilon ( PKC ε). In this study we tested the hypothesis that the delayed onset, PKC ε‐mediated, component of PGE 2 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 G i‐coupled A 1 adenosine receptor on the nociceptor to generate PKC ε‐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 A 1 adenosine receptors each eliminated the late, but not the early, phase of PGE 2 ‐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 PGE 2 hyperalgesia is not PKC ε‐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.