Involvement of Intracellular Calcium in Morphine Tolerance in Mice

Smith, Forrest L.; Dombrowski, Daniel S.; Dewey, William L.

doi:10.1016/s0091-3057(98)00168-3

Cited by 37 publications

(29 citation statements)

References 44 publications

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“…Yet the loss of morphine's efficacy cannot be attributed to either μ receptor desensitization or downregulation, suggesting that non-opioid mechanisms might be involved. This and other laboratories have demonstrated that the adenylyl cyclase and phosphatidylinositol cascades, as well as various Ca ++ and K + channels, contribute to the expression of morphine tolerance [6,9,24,25,34]. These and other mechanisms could be investigated to determine their possible contribution mediating the decrease in morphine's efficacy in tolerant neonatal and infant rats.…”

Section: Influence Of Chronic Morphine Exposure On Brain and Spinal Cmentioning

confidence: 94%

Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine-tolerant infant rats

2007

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We have previously noted that the antinociceptive efficacy of morphine was significantly decreased in rat pups chronically infused with morphine from implanted osmotic minipumps. In this study, morphine was fully efficacious (i.e., 100% maximum possible effect, %MPE) in the 52 ºC tail-immersion test after a 72-h infusion from implanted saline-filled osmotic minipumps. However, administration of up to 1000 mg/kg s.c. morphine failed to elicit greater than a 27% MPE in rats infused with morphine at 2 mg/kg/h. Morphine was more efficacious when the water bath temperature was decreased to 49 ºC. Experiments were conducted to determine the mechanisms whereby chronic morphine administration leads to a decrease in antinociceptive efficacy. The kappa-opioid antagonist nor-binalorphimine completely blocked the antinociceptive effects of morphine in morphine-infused rat pups. The kappa agonist U50,488 elicited antinociception however, the requirement to use higher doses in morphine-than saline-infused rats indicates that kappa cross-tolerance was present. Thus, in tolerant rats the antinociceptive effects of high doses of morphine appear to be mediated through kappa-opioid receptors. The deltaopioid antagonist naltrindole was inactive in both treatment groups. DAMGO-stimulated [ 35 S]GTPγS and [ 3 H]naloxone binding reveal that the anatomical distribution of the mu-opioid receptor was consistent with that of the adult rat brain. In adult rats, the mu-opioid receptor is desensitized during morphine tolerance. However, desensitization was not evident in P17 rats based on the lack of significant decreases in [ 35 S]GTPγS binding. Furthermore, [ 3 H]naloxone binding indicated a lack of mu receptor downregulation in morphine-tolerant rat pups.

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Section: Influence Of Chronic Morphine Exposure On Brain and Spinal Cmentioning

confidence: 94%

Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine-tolerant infant rats

2007

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“…Control groups receive the same number of placebo pellets. The morphine and placebo pellets were a generous gift of the National Institute on Drug Abuse (NIDA) and their use and doses in rats (two pellets) and mice (one pellet) were carried out according to standard methods (Gardell et al, 2002;Gold et al, 1994;Riba et al, 2002;Schmidt et al, 2002;Smith et al, 1999Smith et al, , 2002Vanderah et al, 2001b;Yoburn et al, 1985). Previous studies have shown that implantation of two morphine pellets (75 mg, free base) results in a steady state of plasma morphine levels by 3 days post-pellet implant, ranging between 86.8±13.1 and 156±45 ng/ml, that was maintained through 12 days post-pellet implant (Gold et al, 1994;Yoburn et al, 1985).…”

Section: Sustained Morphine Administrationmentioning

confidence: 99%

Role of NK-1 neurotransmission in opioid-induced hyperalgesia

King

Gardell

Wang

et al. 2005

Pain

153

128

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Opiates are among the most important drugs for treatment of moderate to severe pain and prolonged opiate administration is often required to treat chronic pain states. We investigated the neurobiological actions of sustained opiate administration revealing paradoxical pronociceptive adaptations associated with NK-1 receptor function. Sustained morphine delivered over 6 days elicited hyperalgesia in rats and mice during the period of opiate delivery. Sustained morphine administration increased substance P (SP) and NK-1 receptor expression in the spinal dorsal horn. Sustained morphine treatment also enhanced capsaicin-evoked SP release in vitro, and increased internalization of NK-1 receptors in response to noxious stimulation. While NK-1 receptor internalization was observed primarily in the superficial laminae of placebo-treated rats, NK-1 receptor internalization was seen in both superficial and deep lamina of the dorsal horn in morphinetreated animals. Morphine-induced hyperalgesia was reversed by spinal administration of an NK-1 receptor antagonist in rats and mice, and was observed in wildtype (NK-1 +/+ ), but not NK-1 receptor knockout (NK-1 −/− ), mice. These data support a critical role for the NK-1 receptor in the expression of sustained morphine-induced hyperalgesia. Additionally, these data indicate that sustained opiate administration induces changes reminiscent of those associated with inflammatory pain. These opiate-induced changes might produce unintended deleterious actions in the course of pain treatment in patients. Understanding of sustained morphine-induced neurochemical changes will help identify approaches that limit the deleterious actions of opiates.

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“…In the next series of experiments, we attempted to further elucidate the functional role of CD38 and explored whether it mediated the action of morphine in either acute antinociception or tolerance by inhibiting its enzymatic pathway. Nicotinamide, an inhibitor of CD38 ADP-ribosyl cyclase activity (Inageda et al, 1995;Berthelier et al, 1998), 8-bromocADPR, a chemical analog of cADPR and cell-permeable competitive antagonist of cADPR (Sethi et al, 1997), and ryanodine, which is an inhibitor of ryanodine receptors at a large doses (Ͼ50 M) (Smith et al, 1999), were used to block the action of cADPR.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous results (Smith et al, 1999) indicated that RyRmediated Ca 2ϩ release from intracellular stores is involved in the action of morphine and the development of tolerance in mice. However, the endogenous second messenger to activate RyR was unknown at that time.…”

Section: Discussionmentioning

confidence: 97%

“…In the present study, we proposed that the CD38 -cADPR-RyR pathway is also involved in the mediation of morphine's antinociceptive actions. This hypothesis is also based on our previous findings that the RyR's Ca 2ϩ release from the ER plays a role in morphine's antinociceptive actions (Smith and Stevens, 1995;Smith et al, 1999). To test this hypothesis, we examined whether administration of a substrate for CD38 altered acute morphine antinociception.…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

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

Hull

Rabender²,

Gabra³

et al. 2010

J Pharmacol Exp Ther

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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.

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Involvement of Intracellular Calcium in Morphine Tolerance in Mice

Cited by 37 publications

References 44 publications

Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine-tolerant infant rats

Role of kappa and delta opioid receptors in mediating morphine-induced antinociception in morphine-tolerant infant rats

Role of NK-1 neurotransmission in opioid-induced hyperalgesia

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

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