Agents that act by different mechanisms modulate the activity of protein kinase CbetaII isozyme in the rat spinal cord during peripheral inflammation.
Hyperalgesia following unilateral complete Freund's adjuvant-induced inflammation was characterized by paw withdrawal latency to thermal stimulus. Paw withdrawal latencies were significantly shorter on the complete Freund's adjuvant-treated paw than on the contralateral paw of the complete Freund's adjuvant- and the sham-treated rats. Total cytosolic protein kinase C activity in the lumbar enlargement was unchanged on the sides of the spinal cord ipsi- and contra-lateral to the inflamed paw. Membrane-associated activities of protein kinase Calpha, protein kinase CbetaI and protein kinase Cgamma did not change significantly on the sides of the cord ipsi- and contra-lateral to the inflammation. However, membrane-associated activity of protein kinase CbetaII was increased in the cord section ipsilateral to the inflammation, suggesting that increased translocation/activation of protein kinase CbetaII is related to thermal hyperalgesia. Dextrorphan (an N-methyl-D-aspartate receptor antagonist), L-703,606 (an NK-1 receptor antagonist) and an antisense oligodeoxynucleotide for a selective knockdown of protein kinase Cbeta, reduced complete Freund's adjuvant-induced hyperalgesia, and reversed significant changes in the membrane activity of protein kinase CbetaII on the spinal cord section ipsilateral to the inflamed paw. Dextrorphan and protein kinase Cbeta antisense oligodeoxynucleotide were effective in reversing complete Freund's adjuvant-induced increase in the activity of protein kinase CbetaII ipsilateral to the inflammation at all the doses tested, but L-703,606 was effective only at the highest dose. Furthermore, in the presence of inflammatory stimulus, dextrorphan and L-703,606 did not alter the activities of membrane-associated protein kinase Calpha, protein kinase CbetaI, and protein kinase Cgamma in the section of the spinal cord ipsi- and contra-lateral to the inflammation. Protein kinase Cbeta antisense oligodeoxynucleotide had no significant effect on the membrane-associated activities of protein kinase Calpha and protein kinase Cgamma, but decreased the activities of both protein kinase CbetaI and protein kinase CbetaII and the expression of protein kinase Cbeta isozyme in the spinal cord. The data provide evidence that a common molecular event that converges to initiate and maintain hyperalgesia may include the translocation and activation of protein kinase CbetaII in the spinal dorsal horn.
Igwe
O J
OJ
Division of Pharmacology, University of Missouri-Kansas City, Kansas City, MO 64108-2784, USA. igweo@umkc.edu
D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D003917:Dextrorphan / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000201:enzymology / Q000473:pathology; D047468:Immunoprecipitation; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology*; D015918:Infusion Pumps, Implantable; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000201:enzymology; D020671:Posterior Horn Cells / Q000201:enzymology / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D064546:Protein Kinase C beta; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000201:enzymology* / Q000473:pathology*
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007527:Isoenzymes; D003917:Dextrorphan; D011493:Protein Kinase C; D064546:Protein Kinase C beta