Pretreatment with protein kinase C activator phorbol 12,13-dibutyrate attenuates the antinociception induced by mu- but not epsilon-opioid receptor agonist in the mouse

Neuroscience. 1997 Jan;76(1):291-8. doi: 10.1016/s0306-4522(96)00354-5.


The effects of pretreatment with a protein kinase C activator, phorbol 12,13-dibutyrate, on antinociception induced by i.c.v.-administered mu-opioid receptor agonist (D-Ala2, NMePhe4, Gly(ol)5) enkephalin (DAMGO) or morphine and epsilon-opioid receptor agonist beta-endorphin were studied in male ICR mice. The tail-flick responses were used for antinociceptive tests. I.c.v. pretreatment with phorbol 12,13-dibutyrate (50 pmol) for 30 or 60 but not 10 min attenuated antinociception induced by i.c.v.-administered DAMGO. I.c.v. pretreatment with phorbol 12,13-dibutyrate (10 and 50 pmol) for 60 min caused a dose-dependent attenuation of DAMGO (19.5 pmol)- or morphine (6.0 nmol)-induced antinociception. The dose-response curve for DAMGO-induced antinociception was shifted to the right by 7.3-fold by i.c.v. pretreatment with phorbol 12,13-dibutyrate (50 pmol) for 60 min. However, the i.c.v.-administered beta-endorphin-induced antinociception was not affected by the same pretreatment with phorbol 12,13-dibutyrate. The attenuation of i.c.v.-administered DAMGO- and morphine-induced antinociception by phorbol 12,13-dibutyrate was reversed by concomitant i.c.v. pretreatment with a selective protein kinase C inhibitor calphostin C. These results suggest that activation of protein kinase C by phorbol 12,13-dibutyrate leads to the desensitization of mu-, but not epsilon-opioid receptor-mediated antinociception. These findings also provide additional evidence for differential intracellular modulation on antinociceptive action of mu- and epsilon-opioid receptor agonists.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics / pharmacology
  • Animals
  • Dose-Response Relationship, Drug
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalins / pharmacology
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Injections, Intraventricular
  • Male
  • Mice
  • Mice, Inbred ICR
  • Naphthalenes / pharmacology
  • Nociceptors / drug effects*
  • Pain Measurement
  • Phorbol 12,13-Dibutyrate / pharmacology*
  • Protein Kinase C / metabolism*
  • Receptors, Opioid / agonists*
  • Receptors, Opioid, mu / agonists*
  • Time Factors
  • beta-Endorphin / pharmacology


  • Analgesics
  • Enkephalins
  • Enzyme Inhibitors
  • Naphthalenes
  • Receptors, Opioid
  • Receptors, Opioid, mu
  • epsilon receptor
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Phorbol 12,13-Dibutyrate
  • beta-Endorphin
  • Protein Kinase C
  • calphostin C