Disruption of acute opioid dependence by antisense oligodeoxynucleotides targeting neurogranin.

Neurogranin has been suggested to serve as a common regulator synchronizing the activities of PKC and CaMKII in acute opioid tolerance. To examine if a similar mechanism exists in acute opioid dependence, we directly targeted neurogranin using antisense oligodeoxynucleotides. Male ICR mice were pretreated with neurogranin antisense or mismatch oligodeoxynucleotides (2 microg/day, i.c.v.) for 3 consecutive days. On Day 4, morphine (100 mg/kg, s.c.) was used to induce dependence, as revealed by naloxone-precipitated withdrawal in saline or mismatch-pretreated mice. Antisense-pretreated mice showed decreased neurogranin expression, lack of morphine-induced phosphorylation of neurogranin and activation of CaMKII and CREB, and absence of naloxone-induced withdrawal jumping. Taken together, these data suggest that neurogranin plays an essential role in acute opioid dependence, possibly by affecting the CaMKII and CREB signaling pathway.