Possible Pharmacotherapy of the Opioid κ Receptor Agonist for Drug Dependence

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<jats:p><jats:bold>A<jats:sc>bstract</jats:sc>: </jats:bold> Because there are few efficacious medications for drug dependence, many clinical trials are being conducted in earnest to find such medications. Considerable evidence has shown that opioid κ receptor agonists attenuate several behavioral responses induced by drugs of abuse. Although this raises the possibility that opioid κ receptor agonists may be useful for the treatment of drug dependence on drugs of abuse, it has been previously reported that treatment with selective opioid κ receptor agonists causes a psychotomimetic effect and dysphoria both in clinical studies and experimental animal models. As a result, we found the novel opioid κ receptor agonist TRK‐820, another chemical class of opioid κ receptor agonist that has a morphinan scaffold unlike prototypical opioid κ receptor agonists, by application of a modified message‐address concept. TRK‐820 showed high selectivity for an opioid κ receptor, and strong agonistic activity in both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> experiments. Like other opioid κ receptor agonists, TRK‐820 could markedly suppress the rewarding effects induced by morphine and cocaine and the discriminative stimulus effect of cocaine. Furthermore, TRK‐820 attenuated the mecamylamine‐precipitated nicotine‐withdrawal aversion in a conditioned place preference paradigm. It is worthwhile to note that unlike prototypical opioid κ receptor agonists, TRK‐820 failed to produce a significant place aversion in rodents at doses that were sufficient to produce significant antinociception. Taken together, these findings indicate that TRK‐820 may be useful for the treatment of drug dependence without any aversive effects.</jats:p>

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