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. 1996 Aug;118(7):1829–1835. doi: 10.1111/j.1476-5381.1996.tb15610.x

Role of protein kinase C in desensitization of spinal delta-opioid-mediated antinociception in the mouse.

M Narita 1, H Mizoguchi 1, J P Kampine 1, L F Tseng 1
PMCID: PMC1909849  PMID: 8842450

Abstract

1. Receptor phosphorylation and down-regulation by protein kinases may be a key event initiating desensitization. The present studies were designed to investigate the effect of a potent protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDBu), on antinociception induced by intrathecal (i.t.) administration of a selective delta-opioid receptor agonist [D-Ala2] deltorphin II in the male ICR mouse and on the specific binding of [3H]-[D-Ser2, Leu5]enkephalin-Thr6 (DSLET), a delta-opioid receptor ligand, in the crude synaptic membrane of the spinal cord. 2. Intrathecal (i.t.) pretreatment with PDBu at low doses, which injected alone did not affect the basal tail-flick latency, dose-dependently attenuated the antinociception induced by i.t. administration of [D-Ala2]deltorphin II. The attenuation of i.t.-administered [D-Ala2] deltorphin II-induced antinociception by PDBu was reversed in a dose-dependent manner by i.t. concomitant pretreatment with a specific PKC inhibitor, calphostin C. 3. In the binding experiment, incubation of the crude synaptic membrane of the spinal cord for 2 h at 25 degrees C with PDBu (0.03 to 10 microM) caused a dose-dependent inhibition of the [3H]-DSLET binding. Scatchard analysis of [3H]-DSLET binding revealed that PDBu at 10 microM displayed a 30.7% reduction in the number of [3H]-DSLET binding sites with no significant change in affinity, compared with the non-treatment control, indicating that the activation of membrane-bound PKC by PDBu causes a decrease in the number of specific delta-opioid agonist binding sites. 4. An i.t. injection of [D-Ala2]deltorphin II produced an acute antinociceptive tolerance to the antinociceptive effect of a subsequent i.t. challenge of [D-Ala2]deltorphin II. Concomitant pretreatment with calphostin C markedly prevented the development of acute tolerance to the i.t.-administered [D-Ala2]deltorphin II-induced antinociception. On the other hand, a highly selective protein kinase A (PKA) inhibitor, KT5720, did not have any effect on the development of acute tolerance to [D-Ala2]deltorphin II antinociception. 5. These findings suggest that a loss of specific delta-agonist binding by the activation of PKC by PDBu is involved in the PDBu-induced antinociceptive unresponsiveness to delta-opioid receptor agonist in the mouse spinal cord. Based on the acute tolerance studies, we propose that PKC, but not PKA, plays an important role in the process of homologous desensitization of the spinal delta-opioid receptor-mediated antinociception.

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Selected References

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  1. Akita Y., Ohno S., Konno Y., Yano A., Suzuki K. Expression and properties of two distinct classes of the phorbol ester receptor family, four conventional protein kinase C types, and a novel protein kinase C. J Biol Chem. 1990 Jan 5;265(1):354–362. [PubMed] [Google Scholar]
  2. Bazzi M. D., Nelsestuen G. L. Properties of the protein kinase C-phorbol ester interaction. Biochemistry. 1989 Apr 18;28(8):3577–3585. doi: 10.1021/bi00434a064. [DOI] [PubMed] [Google Scholar]
  3. Dimitrijević S. M., Ryves W. J., Parker P. J., Evans F. J. Characterization of phorbol ester binding to protein kinase C isotypes. Mol Pharmacol. 1995 Aug;48(2):259–267. [PubMed] [Google Scholar]
  4. Downward J., Waterfield M. D., Parker P. J. Autophosphorylation and protein kinase C phosphorylation of the epidermal growth factor receptor. Effect on tyrosine kinase activity and ligand binding affinity. J Biol Chem. 1985 Nov 25;260(27):14538–14546. [PubMed] [Google Scholar]
  5. Erspamer V., Melchiorri P., Falconieri-Erspamer G., Negri L., Corsi R., Severini C., Barra D., Simmaco M., Kreil G. Deltorphins: a family of naturally occurring peptides with high affinity and selectivity for delta opioid binding sites. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5188–5192. doi: 10.1073/pnas.86.13.5188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Evans C. J., Keith D. E., Jr, Morrison H., Magendzo K., Edwards R. H. Cloning of a delta opioid receptor by functional expression. Science. 1992 Dec 18;258(5090):1952–1955. doi: 10.1126/science.1335167. [DOI] [PubMed] [Google Scholar]
  7. Fukushima N., Ueda H., Hayashi C., Katayama T., Miyamae T., Misu Y. Species and age-dependent differences of functional coupling between opioid delta-receptor and G-proteins and possible involvement of protein kinase C in striatal membranes. Neurosci Lett. 1994 Jul 18;176(1):55–58. doi: 10.1016/0304-3940(94)90870-2. [DOI] [PubMed] [Google Scholar]
  8. Hannun Y. A., Loomis C. R., Bell R. M. Activation of protein kinase C by Triton X-100 mixed micelles containing diacylglycerol and phosphatidylserine. J Biol Chem. 1985 Aug 25;260(18):10039–10043. [PubMed] [Google Scholar]
  9. Hylden J. L., Wilcox G. L. Intrathecal morphine in mice: a new technique. Eur J Pharmacol. 1980 Oct 17;67(2-3):313–316. doi: 10.1016/0014-2999(80)90515-4. [DOI] [PubMed] [Google Scholar]
  10. Kase H., Iwahashi K., Nakanishi S., Matsuda Y., Yamada K., Takahashi M., Murakata C., Sato A., Kaneko M. K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. Biochem Biophys Res Commun. 1987 Jan 30;142(2):436–440. doi: 10.1016/0006-291x(87)90293-2. [DOI] [PubMed] [Google Scholar]
  11. Kieffer B. L., Befort K., Gaveriaux-Ruff C., Hirth C. G. The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12048–12052. doi: 10.1073/pnas.89.24.12048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kobayashi E., Nakano H., Morimoto M., Tamaoki T. Calphostin C (UCN-1028C), a novel microbial compound, is a highly potent and specific inhibitor of protein kinase C. Biochem Biophys Res Commun. 1989 Mar 15;159(2):548–553. doi: 10.1016/0006-291x(89)90028-4. [DOI] [PubMed] [Google Scholar]
  13. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  14. Mao J., Price D. D., Phillips L. L., Lu J., Mayer D. J. Increases in protein kinase C gamma immunoreactivity in the spinal cord of rats associated with tolerance to the analgesic effects of morphine. Brain Res. 1995 Apr 24;677(2):257–267. doi: 10.1016/0006-8993(95)00161-i. [DOI] [PubMed] [Google Scholar]
  15. Mattia A., Farmer S. C., Takemori A. E., Sultana M., Portoghese P. S., Mosberg H. I., Bowen W. D., Porreca F. Spinal opioid delta antinociception in the mouse: mediation by a 5'-NTII-sensitive delta receptor subtype. J Pharmacol Exp Ther. 1992 Feb;260(2):518–525. [PubMed] [Google Scholar]
  16. Mayer D. J., Mao J., Price D. D. The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain. 1995 Jun;61(3):365–374. doi: 10.1016/0304-3959(95)00023-L. [DOI] [PubMed] [Google Scholar]
  17. Miyamae T., Fukushima N., Misu Y., Ueda H. Delta opioid receptor mediates phospholipase C activation via Gi in Xenopus oocytes. FEBS Lett. 1993 Nov 1;333(3):311–314. doi: 10.1016/0014-5793(93)80677-m. [DOI] [PubMed] [Google Scholar]
  18. Mizoguchi H., Narita M., Nagase H., Tseng L. F. Antisense oligodeoxynucleotide to a delta-opioid receptor blocks the antinociception induced by cold water swimming. Regul Pept. 1995 Oct 20;59(2):255–259. doi: 10.1016/0167-0115(95)00101-g. [DOI] [PubMed] [Google Scholar]
  19. Narita M., Feng Y., Makimura M., Hoskins B., Ho I. K. A protein kinase inhibitor, H-7, inhibits the development of tolerance to opioid antinociception. Eur J Pharmacol. 1994 Dec 27;271(2-3):543–545. doi: 10.1016/0014-2999(94)90817-6. [DOI] [PubMed] [Google Scholar]
  20. Narita M., Feng Y., Makimura M., Hoskins B., Ho I. K. Repeated administration of opioids alters characteristics of membrane-bound phorbol ester binding in rat brain. Eur J Pharmacol. 1994 Dec 27;271(2-3):547–550. doi: 10.1016/0014-2999(94)90818-4. [DOI] [PubMed] [Google Scholar]
  21. Narita M., Makimura M., Feng Y., Hoskins B., Ho I. K. Influence of chronic morphine treatment on protein kinase C activity: comparison with butorphanol and implication for opioid tolerance. Brain Res. 1994 Jul 4;650(1):175–179. doi: 10.1016/0006-8993(94)90224-0. [DOI] [PubMed] [Google Scholar]
  22. Narita M., Tseng L. F. Stimulation of spinal delta-opioid receptors in mice selectively enhances the attenuation of delta-opioid receptor-mediated antinociception by antisense oligodeoxynucleotide. Eur J Pharmacol. 1995 Sep 15;284(1-2):185–189. doi: 10.1016/0014-2999(95)00414-g. [DOI] [PubMed] [Google Scholar]
  23. Nestler E. J. Molecular mechanisms of drug addiction. J Neurosci. 1992 Jul;12(7):2439–2450. doi: 10.1523/JNEUROSCI.12-07-02439.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nestler E. J., Tallman J. F. Chronic morphine treatment increases cyclic AMP-dependent protein kinase activity in the rat locus coeruleus. Mol Pharmacol. 1988 Feb;33(2):127–132. [PubMed] [Google Scholar]
  25. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992 Oct 23;258(5082):607–614. doi: 10.1126/science.1411571. [DOI] [PubMed] [Google Scholar]
  26. Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986 Jul 18;233(4761):305–312. doi: 10.1126/science.3014651. [DOI] [PubMed] [Google Scholar]
  27. Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
  28. Nomura K., Reuveny E., Narahashi T. Opioid inhibition and desensitization of calcium channel currents in rat dorsal root ganglion neurons. J Pharmacol Exp Ther. 1994 Aug;270(2):466–474. [PubMed] [Google Scholar]
  29. Pei G., Kieffer B. L., Lefkowitz R. J., Freedman N. J. Agonist-dependent phosphorylation of the mouse delta-opioid receptor: involvement of G protein-coupled receptor kinases but not protein kinase C. Mol Pharmacol. 1995 Aug;48(2):173–177. [PubMed] [Google Scholar]
  30. Shahabi N. A., Sharp B. M. Activation of protein kinase C rapidly down-regulates naloxone-resistant receptors for beta-endorphin on U937 cells. J Pharmacol Exp Ther. 1993 Jan;264(1):276–281. [PubMed] [Google Scholar]
  31. Shearman M. S., Sekiguchi K., Nishizuka Y. Modulation of ion channel activity: a key function of the protein kinase C enzyme family. Pharmacol Rev. 1989 Jun;41(2):211–237. [PubMed] [Google Scholar]
  32. Standifer K. M., Chien C. C., Wahlestedt C., Brown G. P., Pasternak G. W. Selective loss of delta opioid analgesia and binding by antisense oligodeoxynucleotides to a delta opioid receptor. Neuron. 1994 Apr;12(4):805–810. doi: 10.1016/0896-6273(94)90333-6. [DOI] [PubMed] [Google Scholar]
  33. Tseng L. F., Collins K. A. Spinal involvement of both dynorphin A and Met-enkephalin in the antinociception induced by intracerebroventricularly administered bremazocine but not morphine in the mouse. J Pharmacol Exp Ther. 1993 Sep;266(3):1430–1438. [PubMed] [Google Scholar]
  34. Tseng L. F., Narita M., Kampine J. P. Pretreatment with beta-endorphin facilitates the attenuation of delta-opioid receptor-mediated antinociception caused by delta-opioid receptor antisense oligodeoxynucleotide. Eur J Pharmacol. 1995 Dec 12;287(2):169–172. doi: 10.1016/0014-2999(95)00587-0. [DOI] [PubMed] [Google Scholar]
  35. Ueda H., Miyamae T., Fukushima N., Misu Y. Protein kinase inhibitor potentiates opioid delta-receptor currents in Xenopus oocytes. Neuroreport. 1994 Oct 3;5(15):1985–1988. doi: 10.1097/00001756-199410000-00037. [DOI] [PubMed] [Google Scholar]
  36. Ueda H., Miyamae T., Hayashi C., Watanabe S., Fukushima N., Sasaki Y., Iwamura T., Misu Y. Protein kinase C involvement in homologous desensitization of delta-opioid receptor coupled to Gi1-phospholipase C activation in Xenopus oocytes. J Neurosci. 1995 Nov;15(11):7485–7499. doi: 10.1523/JNEUROSCI.15-11-07485.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Yang J., Tsien R. W. Enhancement of N- and L-type calcium channel currents by protein kinase C in frog sympathetic neurons. Neuron. 1993 Feb;10(2):127–136. doi: 10.1016/0896-6273(93)90305-b. [DOI] [PubMed] [Google Scholar]

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