title: Curcumin attenuates opioid tolerance and dependence by inhibiting Ca2+/calmodulin-dependent protein kinase II α activity.
abstract: 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 Ca(2+)/calmodulin-dependent protein kinase II α (CaMKIIα), a protein kinase that has been previously proposed to be critical for opioid tolerance and dependence. In this study, we used state-of-the-art polymeric formulation technology to produce poly(lactic-co-glycolic acid) (PLGA)-curcumin nanoparticles (nanocurcumin) to overcome the drug's poor solubility and bioavailability, which has made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGA-curcumin nanoparticles reduced the dose requirement by 11- to 33-fold. Pretreatment with PLGA-curcumin (by mouth) prevented the development of opioid tolerance and dependence in a dose-dependent manner, with ED50 values of 3.9 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.
authors.affiliation: Department of Biopharmaceutical Sciences (X.H., F.H., Y.L., Z.J.W.), Cancer Center (Z.J.W.), and Department of Chemical Engineering (M.S., Y.L.), University of Illinois, Chicago, Illinois.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Biopharmaceutical Sciences (X.H., F.H., Y.L., Z.J.W.), Cancer Center (Z.J.W.), and Department of Chemical Engineering (M.S., Y.L.), University of Illinois, Chicago, Illinois.
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Biopharmaceutical Sciences (X.H., F.H., Y.L., Z.J.W.), Cancer Center (Z.J.W.), and Department of Chemical Engineering (M.S., Y.L.), University of Illinois, Chicago, Illinois.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Szymusiak
authors.affiliation: Department of Biopharmaceutical Sciences (X.H., F.H., Y.L., Z.J.W.), Cancer Center (Z.J.W.), and Department of Chemical Engineering (M.S., Y.L.), University of Illinois, Chicago, Illinois zjwang@uic.edu liuying@uic.edu.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biopharmaceutical Sciences (X.H., F.H., Y.L., Z.J.W.), Cancer Center (Z.J.W.), and Department of Chemical Engineering (M.S., Y.L.), University of Illinois, Chicago, Illinois zjwang@uic.edu liuying@uic.edu.
authors.forename: Zaijie Jim
authors.initials: ZJ
authors.lastname: Wang
mesh_terms: D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003474:Curcumin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019344:Lactic Acid / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000008:administration & dosage*; D011100:Polyglycolic Acid / Q000008:administration & dosage*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003474:Curcumin