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Vol. 293, Issue 2, 662-669, May 2000

Protein Kinase C-Mediated Acute Tolerance to Peripheral µ-Opioid Analgesia in the Bradykinin-Nociception Test in Mice1

Makoto Inoue and Hiroshi Ueda

Department of Molecular Pharmacology and Neuroscience, Nagasaki University School of Pharmaceutical Sciences, Nagasaki, Japan

We studied the acute tolerance liability of peripheral opioid analgesia in mice. The analgesia was assessed by the inhibition of bradykinin (BK)-induced nociceptive action by using a newly developed flexor reflex paradigm. Morphine [intraplantarly (i.pl.)] given ipsilaterally to BK showed a dose-dependent reduction of the BK (2 pmol) responses, whereas the administration of 10 nmol of morphine into the contralateral side failed to show any significant analgesic effects. Furthermore, DAMGO ([D-Ala2,MePhe4,Gly-ol5]-enkephalin), a µ-opioid receptor (MOR) agonist, and U-69593, a kappa -opioid receptor (KOR) agonist, but not DSLET ([D-Ser2]Leu-enkephalin-Thr6), a delta -opioid receptor agonist, showed similar analgesia on the BK responses. The morphine- or U-69593 [(5alpha ,7alpha ,8beta )-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8yl] benzeneacetamide]-induced analgesia was markedly attenuated by the intrathecal injection of each antisense oligodeoxynucleotide for the MOR or KOR, respectively, suggesting that these peripheral analgesia are mediated through MORs and KORs located on nociceptor endings, respectively. As BK response was completely recovered to the control level 4 h after morphine (3 nmol i.pl.) or U-69593 (10 nmol i.pl.) administration, these compounds were challenged again to see the inhibition of BK responses. Although morphine analgesia by the second challenge was markedly attenuated, U-69593 analgesia was not. The attenuated morphine analgesia was completely reversed by the pretreatment of calphostin C, Go6976, or HBDDE, a protein kinase C inhibitor, but not by KT-5720, a protein kinase A inhibitor. These results suggest that selective acute tolerance of peripheral morphine analgesia, but not U-69593 analgesia, through MORs and KORs located on polymodal nociceptors, respectively, in the bradykinin-nociception test in mice was mediated through protein kinase C activation.

1 Parts of this study were supported by Grants-in-Aid from the Ministry of Education, Science, Culture and Sports of Japan, and a grant from The Suzuken Memorial Foundation. M.I. is a Research Fellow of the Japan Society for the Promotion of Science.

0022-3565/00/2932-0662$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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