title: Further confirmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia.
abstract: Recent evidence has suggested that cAMP plays a role as a second messenger in the decrease in nociceptive threshold (or hyperalgesia) produced by agents acting on primary afferent terminals. In support of this hypothesis we report that intradermal injection of a direct activator of adenyl cyclase, forskolin, produces a dose-dependent hyperalgesia in the rat. The duration of this hyperalgesia was prolonged by the phosphodiesterase inhibitors, isobutylmethylxanthine and rolipram. Forskolin hyperalgesia was antagonized by the Rp isomer of cyclic adenosine-3'5'-monophosphothioate, an analog of cAMP that prevents the phosphorylation of the cAMP protein kinase. The Rp isomer of cyclic adenosine-3'5'-monophosphothioate also inhibited the hyperalgesia induced by a membrane-permeable analogue of cAMP, 8-bromocyclic adenosine monophosphate, as well as the hyperalgesia induced by agents that are presumed to act directly on primary afferent nociceptors: prostaglandin E2, prostaglandin I2, (8R,15S)-dihydroxyicosa(5E-9,11,13Z)tetraenoic acid; and the adenosine A2-agonist 2-phenylaminoadenosine. Although the cAMP second messenger system contributes to primary afferent hyperalgesia, we found no evidence for a contribution of protein kinase C. Thus, hyperalgesia induced by prostaglandin E2, prostacyclin (prostaglandin I2), (8R,15S)-dihydroxyicosa(5E-9,11,13Z)tetraenoic acid, the adenosine A2-agonist 2-phenylaminoadenosine, 8-bromocyclic adenosine monophosphate and the direct activator of adenyl cyclase, forskolin, were not significantly attenuated by the selective inhibition of protein kinase C by the 19-31 fragment of protein kinase C. Two other inhibitors of protein kinase C, sphingosine and staurosporine, also failed to attenuate prostaglandin E2-induced hyperalgesia.
authors.affiliation: Department of Medicine, University of California, San Francisco 94143-0724.
authors.forename: Y O
authors.initials: YO
authors.lastname: Taiwo
authors.forename: J D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000633:toxicity; D000241:Adenosine / Q000031:analogs & derivatives / Q000633:toxicity; D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D005576:Colforsin / Q000633:toxicity; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000502:physiology* / Q000633:toxicity; D015232:Dinoprostone / Q000633:toxicity; D011464:Epoprostenol / Q000633:toxicity; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D011760:Pyrrolidinones / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D020889:Rolipram; D015290:Second Messenger Systems / Q000187:drug effects; D012684:Sensory Thresholds / Q000187:drug effects; D013873:Thionucleotides / Q000633:toxicity
chemical_list: D011760:Pyrrolidinones; D013873:Thionucleotides; D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D011464:Epoprostenol; D000242:Cyclic AMP; D011494:Protein Kinases; D000262:Adenylyl Cyclases; C026708:2-phenylaminoadenosine; D020889:Rolipram; D000241:Adenosine; D015232:Dinoprostone; D015056:1-Methyl-3-isobutylxanthine