Reduced development of tolerance to the analgesic effects of morphine and clonidine in PKC gamma mutant mice

Pain. 2001 Dec;94(3):245-253. doi: 10.1016/S0304-3959(01)00353-0.


A variety of second messenger systems have been implicated in the intracellular mechanisms of tolerance development to the analgesic actions of morphine, a mu opioid, and clonidine, an alpha-2 adrenergic receptor agonist. Here, we studied mice that carry a null mutation in the gene encoding a neuronal specific isoform of protein kinase C (PKC), namely, PKC gamma. We used the tail-flick test to construct dose-response curves before and 4 days after chronic morphine (75-mg pellets, subcutaneously (s.c.)) or clonidine treatment (0.3mg/kg, s.c., twice daily). Baseline tail-flick latencies did not differ in PKC gamma mutant and wild-type mice (3-4s). Both morphine and clonidine produced a dose-dependent suppression of the tail-flick response with an ED(50) (effective dose resulting in a 50% reduction of the control response) value (2.0mg/kg for morphine and 0.1mg/kg for clonidine) that was similar for naive mutant and wild-type mice. In contrast, after 4 days of drug delivery, mutant mice showed significantly less rightward shift in the dose-response curve to morphine (six-fold for wild-type and three-fold for mutant mice) and to clonidine (five-fold for wild-type and no shift for the mutant mice). These results indicate that PKC gamma contributes to the development of tolerance to the analgesic effects of both morphine and clonidine. Chronic morphine treatment can also result in sensitization of spinal cord neurons and increased pain behaviors following a noxious insult. To assess the contribution of PKC gamma to this process, we studied the responses of wild-type and mutant mice to an intraplantar injection of formalin (a model of persistent pain) following chronic morphine treatment. Although morphine tolerance increased formalin-evoked persistent pain behavior and Fos-LI in wild-type mice, there was no difference between placebo- and morphine-treated mutant mice, suggesting that PKC gamma also contributes to chronic morphine-induced changes in nociceptive processing.

Publication types

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

MeSH terms

  • Analgesics / pharmacology*
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Clonidine / pharmacology*
  • Drug Tolerance / genetics
  • Hyperalgesia / drug therapy
  • Isoenzymes / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Morphine / pharmacology*
  • Morphine Dependence / enzymology
  • Morphine Dependence / genetics
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Pain Measurement / drug effects
  • Protein Kinase C / genetics*


  • Analgesics
  • Analgesics, Opioid
  • Isoenzymes
  • Narcotic Antagonists
  • Naloxone
  • Morphine
  • protein kinase C gamma
  • Protein Kinase C
  • Clonidine