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, due to 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. Pretreated with haloperidol (0.2-1.0mg/kg; i.p.) prevented the development of morphine tolerance and dependence in a dose dependent manner. Acute treatment with haloperidol (0.06-0.60mg/kg, i.p.) dose-dependently reversed the established morphine antinociceptive tolerance and physical dependence. Correlating with behavioral effects, pretreatment or acute treatment with haloperidol dose-dependently inhibited morphine induced up-regulation of supraspinal and spinal CaMKII?activity. Moreover, haloperidol given orally was also effective in attenuating morphine-induced CaMKII?activity, antinociceptive tolerance, and physical dependence. Taken together, these data suggest that haloperidol attenuates opioid tolerance and dependence by suppressing CaMKII activity. Since haloperidol is a clinically used drug that can be taken orally, we propose the drug may be of use in attenuating opioid tolerance and dependence.
- Received September 24, 2010.
- Revision received March 23, 2011.
- Accepted March 23, 2011.
- The American Society for Pharmacology and Experimental Therapeutics