Morphine post-addict rats were found to self-administer the kappa opioid agonist/mu antagonist analgesics nalbuphine, butorphanol and pentazocine and establish kappa opioid dependence; withdrawal of these kappa opioids was associated with a mild """"""""kappa-withdrawal"""""""" syndrome. Furthermore, it is presumed that the overall potential for abuse associated with use of these kappa opioids is generally low. Morphine and methadone post-addict rats exhibit a long-lived protracted abstinence state reflected by an abnormal decrease in EEG voltage output and by behavioral arousal in response to morphine challenges, rather than EEG slow-wave bursts and stuporous behavior. These abnormal EEG and behavioral characteristics of protracted abstinence prevail for several months. Relapse to heroin use is very common following the detoxification of heroin addicts or methadone maintained individuals. It was shown that following methadone detoxification, signs and symptoms of a protracted abstinence state persist for several months. It has been suggested that the relief of these protracted abstinence symptoms by illicit opioid administration may be a primary reason for relapse to opioid use by individuals undergoing detoxification. We are hypothesizing, therefore, that kappa opioid maintenance, in contrast to methadone (mu) maintenance, may lead, upon withdrawal, to a protracted abstinence syndrome of lower severity and to a lower tendency for relapse to morphine self-administration; thus, providing better conditions for achieving a drug-free state. The present competing continuation renewal application is designed to test this hypothesis. Rats that are self-administering morphine to maintain their own dependence will be prepared. They will be subsequently maintained on methadone (mu agonist) or, following morphine withdrawal, on pentazocine, malbuphine and butorphanol (kappa agonists). Upon withdrawal of these opioids, the intensities of the early and the protracted abstinence syndromes, as well as the tendency to relapse to morphine self-administration, will be studied and compared. This preclinical study will, therefore, enhance our knowledge of the comparative pharmacodynamics of abstinence and relapse to morphine self-administration, following maintenance on methadone, mu vs. kappa opioids. If the results were found to support our hypothesis, then kappa opioid maintenance may offer a pharmacotherapeutic modality with, presumably, low relapse rate following detoxification.
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