Prevention of fentanyl-induced delayed pronociceptive effects in mice lacking the protein kinase Cgamma gene.
It has recently been reported in several nociceptive models of rats that the antinociceptive effect of fentanyl, an opioid analgesic widely used in the management of per-operative pain, was followed by paradoxical delayed hyperalgesia dependent on N-methyl-D-aspartate (NMDA) mechanisms. Events upstream of the NMDA receptor, especially the activation of the protein kinase Cgamma (PKCgamma), have been involved in the persistence of pain states associated with central sensitisation. In order to evaluate the contribution of the PKCgamma in early and delayed fentanyl nociceptive responses, we studied these effects in knock-out mice deficient in such a protein. We found that fentanyl antinociception was followed by the spontaneous appearance of prolonged hyperalgesia in the paw pressure and formalin tests, and allodynia in the Von Frey paradigm. In PKCgamma deficient mice, an enhancement of the early fentanyl antinociceptive effects was observed, as well as a complete prevention of the fentanyl delayed hyperalgesic/allodynic effects. Finally, naloxone administration in mice that had recovered their pre-fentanyl nociceptive threshold, precipitated hyperalgesia/allodynia in wild-type but not in mutant mice. This study identifies the PKCgamma as a key element that links opioid receptor activation with the recruitment of opposite systems to opioid analgesia involved in a physiological compensatory pain enhancement.
Célérier
Evelyne
E
Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, C/Doctor Aiguader 80, E-08003 Barcelona, Spain. e_celerier@yahoo.com
Simonnet
Guy
G
Maldonado
Rafael
R
D000818:Animals; D005283:Fentanyl / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics; D011930:Reaction Time / Q000187:drug effects* / Q000235:genetics*
C087857:protein kinase C gamma; D011493:Protein Kinase C; D005283:Fentanyl