Exaggerated nociceptive responses on morphine withdrawal: roles of protein kinase C ε and γ

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 ε and γ 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 ε, but not an inhibitor of calcium-dependent PKC γ, blocked withdrawal hyperresponsiveness of the sVRP. Similarly, in vivo in 7-day-old rat pups, inhibition of PKC ε, but not PKC γ, prevented thermal hyperalgesia precipitated by naloxone at 30 min post-morphine. In contrast, thermal hyperalgesia during spontaneous withdrawal was inhibited by both PKC ε and γ 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 ε translocation, followed by a later phase involving spinal sensitization mediated by PKC γ.