Exaggerated nociceptive responses on morphine withdrawal: roles of protein kinase C epsilon and gamma.
On withdrawal from opioids many patients experience a heightened sensitivity to stimuli and an exaggerated pain response. The phenomenon has been little studied in infants. We present evidence that in postnatal day 7 rats an exaggerated nociceptive ventral root response of spinal cords in vitro and withdrawal-associated thermal hyperalgesia in vivo are dependent on protein kinase C (PKC), and we document the roles of PKC and gamma isozymes. In vitro, the slow ventral root potential (sVRP) is a nociceptive-related response in spinal cord that is depressed by morphine and recovers to levels significantly above control on administration of naloxone. A broad-spectrum PKC antagonist, GF109213X, blocked withdrawal hyperresponsiveness of the sVRP whereas an antagonist specific to Ca(++)-dependent isozymes, Go69076, did not. Consistent with this finding, a specific peptide inhibitor of calcium-independent PKC, but not an inhibitor of calcium-dependent PKC gamma, blocked withdrawal hyperresponsiveness of the sVRP. Similarly, in vivo in 7-day-old rat pups, inhibition of PKC, but not PKC gamma, prevented thermal hyperalgesia precipitated by naloxone at 30 min post-morphine. In contrast, thermal hyperalgesia during spontaneous withdrawal was inhibited by both PKC and gamma inhibitors. The consistency between the in vivo and in vitro findings with respect to naloxone-precipitated withdrawal provides further evidence that the sVRP reflects nociceptive neurotransmission. In addition the difference between naloxone-precipitated and spontaneous withdrawal in vivo suggests that in postnatal day 7 rats, morphine exposure produces an early phase of primary afferent sensitization dependent upon PKC translocation, followed by a later phase involving spinal sensitization mediated by PKC gamma.
Sweitzer
Sarah M
SM
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USA. sweitzer@med.sc.edu
Wong
Shirley M E
SM
Tjolsen
Arne
A
Allen
Caroline P
CP
Mochly-Rosen
Daria
D
Kendig
Joan J
JJ
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000209:etiology*; D010455:Peptides / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D051744:Protein Kinase C-epsilon; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000502:physiology; D013126:Spinal Nerve Roots / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000201:enzymology / Q000503:physiopathology*
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D009292:Narcotic Antagonists; D009294:Narcotics; D010455:Peptides; D009270:Naloxone; D009020:Morphine; C497257:Prkce protein, rat; C087857:protein kinase C gamma; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; C070515:bisindolylmaleimide I