Role of CD38 in Morphine Tolerance

Abstract

Although CD38 has been found in the brain, its role in neuronal signal transduction has not been fully characterized. CD38’s product, cyclic ADP ribose (cADPr), modulates intracellular calcium through the ryanodine receptor on the endoplasmic reticulum. Increased basal levels of intracellular calcium have been reported in opioid tolerant cells; therefore we hypothesize that the CD38 pathway may be one of the controls of intracellular calcium altered by morphine. We tested this hypothesis by blocking three separate parts of the CD38-cADPr-Ryanodine pathway. Nicotinamide, a bi-product of the ribosylcyclase activity of CD38, was used in excess as an inhibitor of CD38, the cADPr analog 8-bromo-cADPr was used as a competitive inhibitor of cADPR, and ryanodine was used to block the ryanodine receptor. Swiss-Webster mice were implanted with a 75mg pellet of morphine for 72 hrs, then exposed to an inhibitor and administered cumulative doses of morphine s.c. Nicotinamide administered i.p. fully reversed a 4.37 fold tolerance and i.c.v. fully reversed a 4.89 fold tolerance. 8-bromo-cADPr administered i.c.v. fully reversed a 4.61 fold tolerance. Ryanodine administered i.c.v. fully reversed a 4.95 fold tolerance. These data indicate that the CD38 pathway is involved in morphine tolerance. Funded by NIH grants: R01-DA-01647, T32-DA-07027, K05-DA-00480, HL-57244, HL-75316, RO1-DA-020836.