Role of CD38, a Cyclic ADP-Ribosylcyclase, in Morphine Antinociception and Tolerance

Abstract

Our previous studies have demonstrated that an increase in intracellular levels of Ca 2ϩ in neurons is an important component of both the antinociception produced by morphine and morphine's tolerance. The present study tested the hypothesis that the Ca 2ϩ signaling second messenger, cyclic ADP-ribose (cADPR), derived from CD38 activation participates in morphine antinociception and tolerance. We first showed that morphine's antinociceptive potency was increased by the intracerebroventricular injection of CD38 substrate ␤-NAD ϩ in mice. Furthermore, morphine tolerance was reversed by intracerebroventricular administration of each of three different inhibitors of the CD38 -cADPR-ryanodine receptor Ca 2ϩ signaling pathway. These inhibitors were the ADP-ribosylcyclase inhibitor nicotinamide, cADPR analog 8-bromo-cADPR, and a large dose of ryanodine (Ͼ50 M) that blocks the ryanodine receptor. In CD38 gene knockout [CD38(Ϫ/Ϫ)] mice, the antinociceptive action of morphine was found to be less potent compared with wild-type (WT) mice, as measured by tail-flick response, hypothermia assay, and observations of straub tail. However, there was no difference in locomotor activation between CD38(Ϫ/Ϫ) and WT animals. It was also found that less tolerance to morphine developed in CD38(Ϫ/Ϫ) mice compared with WT animals. These results indicate that cADRP-ryanodine receptor Ca 2ϩ signaling associated with CD38 plays an important role in morphine tolerance.

Bioinformatics analysis of gene and microRNA targets for fibromyalgia

“…In addition, Sadeghi et al found that phenytoin may inhibit Ca2+ influx through regulate cyclase activity of CD38 and cADPR (cyclic adenosine diphosphate ribose), and then play an anticonvulsant role in the treatment of depression (33). Hull et al found that CD38 may be involved in morphine tolerance and pain receptor abnormalities by regulating CD38-cADPR-ryanodine receptor Ca (2+) signalling pathway (34).…”