CHRONIC INHIBITION OF INTRACELLULAR CA2-KINASE-C ACTIVATION SIGNIFICANTLY REDUCES THE DEVELOPMENT OF MORPHINE-DEPENDENCE( RELEASE OR PROTEIN)

We have previously shown that chronic antagonism of metabotropic gluta mate receptors in the brain attenuates naloxone-precipitated withdrawa l symptoms in rats treated chronically with subcutaneous (s.c.) morphi ne. Several subtypes of metabotropic glutamate receptors are directly linked, through a guanine nucleotide regulatory protein, to the phosph atidylinositol (PI) second messenger system. In the present investigat ion, we assessed the effect of inhibiting the products of PI hydrolysi s on the development of opioid dependence. Thus, concurrently with sub cutaneous morphine, we infused intracerebroventricularly (i.c.v.) in r ats, various doses of chelerythrine, which selectively inhibits the ac tivation of protein kinase C, and thapsigargin, which inhibits the rel ease of intracellular Ca2+ when given chronically. Both chelerythrine and thapsigargin reduced the severity of naloxone-precipitated abstine nce symptoms when infused i.c.v. at a dose of 10 nmol/day. A single in jection of either chelerythrine or thapsigargin immediately prior to t he precipitation of withdrawal failed to decrease the severity of abst inence symptoms. Our results suggest that by chronically inhibiting ac tivity of the phosphatidylinositol system, the development of morphine dependence can be attenuated.