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: Y O Taiwo, J D Levine
• Journal: Neuroscience (Neuroscience) Vol. 44 Issue 1 Pg. 131-5 ( 1991) ISSN: 0306-4522 [Print] United States
• PMID: 1722888 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Pyrrolidinones
• Thionucleotides
• Colforsin
• adenosine-3',5'-cyclic phosphorothioate
• Epoprostenol
• Cyclic AMP
• Protein Kinases
• Adenylyl Cyclases
• 2-phenylaminoadenosine
• Rolipram
• Adenosine
• Dinoprostone
• 1-Methyl-3-isobutylxanthine

Topics

• 1-Methyl-3-isobutylxanthine (toxicity)
• Adenosine (analogs & derivatives, toxicity)
• Adenylyl Cyclases (physiology)
• Animals
• Colforsin (toxicity)
• Cyclic AMP (analogs & derivatives, physiology, toxicity)
• Dinoprostone (toxicity)
• Epoprostenol (toxicity)
• Hyperalgesia (chemically induced, enzymology, physiopathology)
• Male
• Phosphorylation
• Protein Kinases (physiology)
• Pyrrolidinones (toxicity)
• Rats
• Rats, Inbred Strains
• Rolipram
• Second Messenger Systems (drug effects)
• Sensory Thresholds (drug effects)
• Thionucleotides (toxicity)