Role of CD38, a cyclic ADP-ribosylcyclase, in morphine antinociception and tolerance.
Our previous studies have demonstrated that an increase in intracellular levels of Ca(2+) 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(2+) 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 beta-NAD(+) in mice. Furthermore, morphine tolerance was reversed by intracerebroventricular administration of each of three different inhibitors of the CD38-cADPR-ryanodine receptor Ca(2+) signaling pathway. These inhibitors were the ADP-ribosylcyclase inhibitor nicotinamide, cADPR analog 8-bromo-cADPR, and a large dose of ryanodine (>50 muM) that blocks the ryanodine receptor. In CD38 gene knockout [CD38(-/-)] 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(-/-) and WT animals. It was also found that less tolerance to morphine developed in CD38(-/-) mice compared with WT animals. These results indicate that cADRP-ryanodine receptor Ca(2+) signaling associated with CD38 plays an important role in morphine tolerance.
Hull
Lynn C
LC
Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA.
Rabender
Christopher
C
Gabra
Bichoy H
BH
Zhang
Fan
F
Li
Pin-Lan
PL
Dewey
William L
WL
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics* / Q000502:physiology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006358:Hot Temperature; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D007101:Immersion / Q000503:physiopathology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009243:NAD / Q000494:pharmacology; D009536:Niacinamide / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects
D000701:Analgesics, Opioid; D019837:Ryanodine Receptor Calcium Release Channel; D009243:NAD; D036563:Cyclic ADP-Ribose; D009536:Niacinamide; D009020:Morphine; D051997:ADP-ribosyl Cyclase 1