Abstract
Previous studies from our laboratory and others have implicated a critical role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in opioid tolerance and dependence. Translational research targeting the CaMKII pathway is challenging, if not impossible, because of a lack of selective inhibitors. We discovered in a preliminary study that haloperidol, a butyrophenone antipsychotic drug, inhibited CaMKII, which led us to hypothesize that haloperidol can attenuate opioid tolerance and dependence by inhibiting CaMKII. The hypothesis was tested in two rodent models of opioid tolerance and dependence. Pretreatment with haloperidol (0.2–1.0 mg/kg i.p.) prevented the development of morphine tolerance and dependence in a dose-dependent manner. Short-term treatment with haloperidol (0.06–0.60 mg/kg i.p.) dose-dependently reversed the established morphine-antinociceptive tolerance and physical dependence. Correlating with behavioral effects, pretreatment or short-term treatment with haloperidol dose-dependently inhibited morphine-induced up-regulation of supraspinal and spinal CaMKIIα activity. Moreover, haloperidol given orally was also effective in attenuating morphine-induced CaMKIIα activity, antinociceptive tolerance, and physical dependence. Taken together, these data suggest that haloperidol attenuates opioid tolerance and dependence by suppressing CaMKII activity. Because haloperidol is a clinically used drug that can be taken orally, we propose that the drug may be of use in attenuating opioid tolerance and dependence.
Footnotes
This work was supported in part by the National Institutes of Health National Heart, Lung and Blood Institute [Grant HL098141]; and the National Institutes of Health National Center for Complementary and Alternative Medicine [Grant AT003647]. Y.C. was supported by a University of Illinois predoctoral scholarship.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.175539.
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ABBREVIATIONS:
- CaMKII
- Ca2+/calmodulin-dependent protein kinase II
- NMDA
- N-methyl-d-aspartate
- μOR
- the μ-opioid receptor
- MPE
- maximal possible effect
- MK801
- (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate.
- Received September 24, 2010.
- Accepted March 23, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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