MCW Office of Technology Development

Leon Tseng, PhD

Opiates (e.g. morphine and heroin) produce potent analgesic effects via the stimulation of μ-opioid receptors in the central nervous system. Opiates also invariably cause opiate addiction which is also mediated by μ-opioid receptor activation. Thus, both analgesia and addiction produced by opiates are commonly mediated by μ-opioid receptor activation. However, the analgesic effect produced by opiates are mediated by the activation of the descending pain controls, while the addictive effects produced by opiates are mediated by the mesolimbic dopaminergic system, which involves the release of dopamine. Similarly, chronic tobacco use also produces nicotine addiction. Evidence suggests that nicotine-induced release of dopamine in the mesolimbic reinforcement pathway is essential to nicotine addiction. Naturally occurring morphine, isolated from the opium poppy, papaver somniferum, is stereochemically identified as a levorotatory form. The dextrorotatory enantiomer of morphine (i.e. dextro-morphine), which is synthesized from sinomenine, does not have any affinity for μ-opioid receptors and therefore does not produce any μ-opioid receptor mediated pharmacological effects. This invention is based on the discovery that dextro-morphine processes potent anti-addictive properties against morphine- and nicotine-induced addiction.

An unbiased conditioned place preference (CPP) paradigm was used to evaluate the effect of dextro-morphine on the morphine-produced reward in male CD rats. Morphine sulfate (1-10 mg/kg) given intraperitoneally, dose-dependently produced the CPP. Pretreatment with dextro-morphine at a dose of 0.1 to 3 μg/kg given subcutaneously dose-dependently attenuated the morphine-produced CPP. dextro-Morphine given alone did not have any effect of the baseline score of CPP. The attenuation of the morphine-produced CPP was reversed by the pretreatment with a sigma-1 receptor antagonist. This indicates that dextro-morphine attenuated the morphine-produced CPP via the sigma-1 receptor activation. In addition, morphine sulfate at a dose of 5 μg given into posterior nucleus accumbens (Acb) shell produced the marked CPP. Pretreatment with dextro-morphine at a dose of 0.1 to 3 pg given into the same Acb shell dose-dependently attenuated the CPP produced by morphine. Nicotine tartrate at a dose of 20 μg given into Acb shell also produced the marked CPP. The CPP produced by nicotine was attenuated dose-dependently by the pretreatment with 0.03 to 3 pg dextro-morphine given into the Acb shell. Thus, dextro-morphine given either systemically or intracerebral Acb blocks the reinforcement effect produced by morphine or nicotine. These data indicate that dextro-morphine could be developed as a therapeutic treatment for opiate and nicotine addiction.

• Provides a therapy for treating opiate addiction
• Provides a therapy for treating nicotine addiction
• Dextro-morphine molecule does not produce opiate analgesic effects

Preclinical animal studies