Protein kinase c ϵ and γ: roles in age-specific modulation of acute opioid-withdrawal allodynia

Abstract

Acute morphine withdrawal results in enhanced responsiveness to noxious stimulation in adult humans and rodents. This study extends these findings by demonstrating that acute morphine withdrawal produces allodynia in neonatal rats that is dependent on the translocation of protein kinase C ϵ and γ (ϵPKC and γPKC, respectively) in a developmentally specific manner. Basal expression of ϵPKC in dorsal root ganglia, and γPKC in lamina II of the lumbar spinal cord, were lower in postnatal day 7 (P7) compared with P21 rats. ϵPKC immunoreactivity increased in P7 rats at 4 hours after acute administration of morphine, whereas ϵPKC immunoreactivity decreased at 4 hours in P21 rats. In contrast to ϵPKC, there was a loss of γPKC immunoreactivity following morphine administration in both P7 and P21 rats. To determine whether ϵ and γPKC contribute to acute withdrawal-induced allodynia in neonatal rats, isozyme-specific inhibitors of ϵ and γPKC translocation were administered before or after morphine administration. Naloxone was used to precipitate withdrawal at either 30 or 120 minutes after morphine, or animals were allowed to undergo natural withdrawal from a single dose of morphine. Inhibition of ϵ but not γPKC prevented naloxone-precipitated allodynia 30 minutes after morphine administration in P7 rats. In contrast, both ϵ and γPKC inhibitors attenuated naloxone-precipitated allodynia in P21 rats. Allodynia was attenuated in P7 and P21 rats by administration of either ϵ or γPKC inhibitor when withdrawal was precipitated at 2 hours after morphine or animals underwent natural withdrawal. This work demonstrates that the role of ϵ and γPKC in acute withdrawal-induced allodynia is developmentally regulated in a temporally specific manner.