Effects Of κ-Agonists On Dependece Of Opioid

Drug abuse continues to be a major public health problem,and no consistently effective pharmacotherapy has been developed.There is increasing evidence that highly selectiveκagonist (-)U50,488H can reduce cocaine dependence,however,the effects of(-)U50,488H on heroin dependence was not clear.In present study,stable heroin self-administration behavior was established to mimic human drug-taking behavior,and we demonstrated that the traditional highly selectiveκagonist(-)U50,488H significantly attenuated heroin-induced self-administration behavior indicated by apparent reduction in the number of infusions of heroin.These data suggest that it is possible that common molecular mechanism underlying the actions of different drugs (heroin,cocaine) andκagonists can be used to reduce drug abuse.However,highly selectiveκagonists produced transient sedation and emesis,although tolerance developed to these effects during chronic treatment.These findings suggest that highly selectiveκagonists may decrease drug-taking by producing a general disruption of behavior rather than a selective decrease in the reinforcing effects of cocaine.Recently,Archer et al reported thatκ/μopioid combinations might be useful for the treatment of cocaine abuse with fewer and less severe side effects.ATPM, ((-)-3-amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride),was found to have mixedκ-andμ-opioid activity and identified to act as a fullκagonist and a partialμagonist by in vitro binding assays.The present study demonstrated that ATPM was able to yield more potent antinociceptive effects than(-)U50,488H.It was further found that the antinociceptive effects of ATPM were mediated byκ- andμ-,but notδ- opioid receptors.Besides its agonist profile on theμreceptor,ATPM also acted as aμantagonist,as measured by its inhibition of morphine-induced antinociception.More importantly,ATPM had a greater ratio of the ED₅₀ value of sedation to that of antinociception than(-)U50,488H(11.8 versus 3.7),indicative of less sedative effect than (-)U50,488H.In addition,ATPM showed less potential to develop antinociceptive tolerance relative to(-)U50,488H.Moreover it dose-dependently inhibited morphine-induced antinociceptive tolerance,and decreased the withdrawal signs induced by naloxone in morphine-dependent mice. On the country,(-)U50,488H has no effect on morphine-induced physical dependence.Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM produced sustained decreases in heroin self-administration.These findings suggest highly selectiveκagonists,such as (-)U50,488H decreased drug-taking behavior but only at doses that also produced severe undesirable side effects,whereasκagonists withμreceptor activity,such as ATPM reduced drug-taking behavior with fewer and less severe side effects.From these results,we postulated that high-efficacyμagonists withμreceptor activity offer some advantages over highly selectiveκagonists,and may be especially promising as candidate treatments for opioid dependence.