Chronic use of opioid analgesics has been hindered by the development of opioid addiction and tolerance. We have reported that curcumin, a natural flavonoid from the rhizome of Curcuma longa, attenuated opioid tolerance, although the underlying mechanism remains unclear. In this study, we tested the hypothesis that curcumin may inhibit Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα), a protein kinase that have been previously proposed to be critical for opioid tolerance and dependence. In this study, we have employed a state-of-art polymeric formulation technology to produce PLGA-curcumin nanoparticles (nanocurcumin), in order to overcome the drug's poor solubility and bioavailability that have made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGA-curcumin nanoparticles reduced the dose requirement by 11-33 folds. Pretreatment with PLGA-curcumin (p.o.) prevented the development of opioid tolerance and dependence in a dose dependent manner with ED50 of 3.9 mg/kg and 3.2 mg/kg, respectively. PLGA-curcumin dose-dependently attenuated already-established opioid tolerance (ED50= 12.6 mg/kg, p.o.) and dependence (ED50= 3.1 mg/kg, p.o.). Curcumin or PLGA-curcumin did not produce antinociception by itself or affect morphine (1-10 mg/kg) antinociception. Moreover, we found that the behavioral effects of curcumin on opioid tolerance and dependence correlated with its inhibition of morphine-induced CaMKIIα activation in the brain. These results suggest that curcumin may attenuate opioid tolerance and dependence by suppressing CaMKIIα activity.
- The American Society for Pharmacology and Experimental Therapeutics