Cholecystokinin, Non-Selective

Administration of PLGA-curcumin nanoparticles (20 mg/kg p

Administration of PLGA-curcumin nanoparticles (20 mg/kg p.o.) significantly attenuated the established chronic morphine tolerance (77.9 8.8% MPE, < 0.001 versus the morphine group), whereas nanocurcumin at lower doses (6 and 2 mg/kg p.o.) showed marginal effects on morphine tolerance (43.5 17.9% and 17.6 16.0% MPE, > 0.05 from morphine alone) (Fig. effective in preventing and reversing opioid tolerance and dependence in rodent models (Wang et al., 2003; Tang et Fumaric acid al., 2006b). Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is usually a natural flavonoid component found in the rhizome of (Zingiberaceae or ginger family). A number of pharmacological effects have been reported for curcumin, including antioxidant, anti-inflammatory, chemotherapeutic, and possibly even antinociceptive effects (Asher and Spelman, 2013; Marchiani et al., 2014). Several recent publications suggest that long-term treatment with curcumin is effective in attenuating opioid tolerance and dependence, although the underlying mechanism is not obvious (Matsushita and Ueda, 2009; Lin et al., 2011; Liang et al., 2013). Interestingly, curcumin has been recently Fumaric acid found to inhibit the Ca2+-dependent and -impartial kinase activities of CaMKII based on cell-free assays (Mayadevi et al., 2012). We hypothesize that curcumin may attenuate opioid tolerance and dependence by inhibiting CaMKIIin the central nervous system. Despite the numerous reported pharmacologic actions, curcumin is not widely used as a therapeutic agent, likely due to its relatively low solubility and bioavailability (Anand et al., 2007) and lack of understanding of its mechanism of action. With the requirement of high doses in pharmacologic studies and poor solubility, it is difficult to independently confirm pharmacologic actions and ascertain the exact dose producing these effects. We have recently developed several polymeric nanoparticles encapsulating curcumin, including poly(lactic-(pCaMKIIantibody were characterized in transgenic mice (CaMKIIto those of < 0.001) compared with MPE in the control mice pretreated with saline (91.5 4.4% MPE) (Fig. 1A). Mice were treated with unformulated curcumin (20C400 mg/kg p.o.) 15 minutes before the induction dose of morphine. Mice treated with curcumin (20 mg/kg p.o.) developed morphine antinociceptive tolerance (22.6 5.2% MPE versus 91.5 4.4% MPE in the saline group, < 0.001) and displayed a significant quantity of naloxone-precipitated withdrawal jumps (82.7 11.7 versus 13.0 4.9 in Rabbit Polyclonal to CK-1alpha (phospho-Tyr294) the saline group, < 0.001) (Fig. 1). In mice treated with curcumin (200 or 400 mg/kg p.o.), morphine (100 mg/kg) did not produce antinociceptive tolerance (75.9 12.4% and 81.1 7.0% MPE, not significant from your Fumaric acid saline-treated group, < 0.001 versus morphine alone) (Fig. 1). In those mice, naloxone-precipitated withdrawal jumping was significantly reduced (46.3 10.8 and 37.0 12.8 versus 80.4 7.4 in the morphine group, < 0.05 and < 0.01, respectively), suggesting that curcumin at high doses prevented the development of acute morphine tolerance and dependence (Fig. 1). The ED50 of curcumin is usually estimated to be 44.2 mg/kg (tolerance) and 109.0 mg/kg (dependence) (Fig. 3). Open in a separate windows Fig. 1. Prevention of acute opioid tolerance (A) and dependence (B) by curcumin at high doses. Separated groups of six mice were pretreated with curcumin (20, 200, 400 mg/kg p.o.) or saline before the treatment with morphine sulfate (100 mg/kg s.c.) or saline to induce acute opioid tolerance and dependence. Curcumin (200, 400 mg/kg) significantly attenuated opioid antinociceptive tolerance (A) and physical dependence (B), whereas it was not effective at 20 mg/kg. Data are expressed as the mean S.E.M. ***< 0.001 compared with the saline group; #< 0.05; ##< 0.01; ###< 0.001 compared with the morphine (MS) group. Open in a separate windows Fig. 3. Dose-response curve of unformulated curcumin and PLGA-curcumin nanoparticles. Dose-response curves for the effects of unformulated curcumin and PLGA-curcumin nanoparticles around the acute morphine tolerance (A) and dependence (B) were plotted on a log-dose level. ED50 values were calculated based on the dose-response curve. PLGA-curcumin nanoparticles left shifted the dose-response curve and showed higher potency than unconjugated curcumin in preventing both acute morphine tolerance and dependence. PLGA-Curcumin Nanoparticles Prevented Acute Opioid Tolerance. The major problem in.