Stimulation of porphyrin accumulation in chick embryo liver cell cultures by partially purified erythroprotein Academic Article uri icon

Overview

MeSH Major

  • Arachidonic Acid
  • Cytochrome P-450 Enzyme System
  • Environmental Pollutants
  • Polychlorinated Dibenzodioxins

abstract

  • Previous studies from our laboratory and others have implicated a critical role of Ca(2+)/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 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. 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.

publication date

  • January 25, 1974

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1016/0304-4165(74)90345-6

Additional Document Info

start page

  • 164

end page

  • 72

volume

  • 338

number

  • 1