trk-820 and Schizophrenia

Nalfurafine hydrochloride, a kappa-opioid receptor agonist, was approved in January 2009 and released to the market on March 2009 for the indication of "Improvement of pruritus in hemodialysis patients (only for cases resistant to conventional treatments)" in Japan (Brand Name: REMITCH CAPSULES 2.5 microg, Marketing Authorization Holder: Toray Industries, Inc., Distributed by Torii Pharmaceutical Co., Ltd., Co-developed by Japan Tobacco Inc.). In addition to antipruritic effect, nalfurafine hydrochloride showed ameliorating effects on pain, neuropathic pain, drug dependence, schizophrenia and dyskinesia in non-clinical studies. Therefore, nalfurafine hydrochloride may become a useful therapeutic agent for their diseases.

Topics: Analgesics; Animals; Antipruritics; Disease Models, Animal; Drug Tolerance; Dyskinesias; Humans; Mice; Morphinans; Rats; Receptors, Opioid, kappa; Schizophrenia; Spiro Compounds; Substance Withdrawal Syndrome

Abnormalities in dopaminergic and serotonergic neurotransmission in the forebrain are believed to be involved in the underlying mechanism of schizophrenia; therefore, the direct blockade of the receptors associated with these systems is a central strategy for schizophrenia treatment, even though this strategy concurrently produces adverse effects like extrapyramidal effects. Kappa opioid receptors exist extensively in the brain and recent reports have suggested that these receptors are involved in modulating the release of several neurotransmitters including dopamine and serotonin. In the present study, we investigated the effect of TRK-820, (E)-N-[17-(cyclopropylmethyl)-4,5alpha-epoxy-3,14-dihydroxymorphinan-6beta-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride, a selective kappa opioid receptor agonist, on phencyclidine-induced rat behavioral changes and on biochemical changes in the prefrontal cortex. First, TRK-820 dose-dependently inhibited phencyclidine-induced rat hyperlocomotion, which is one of the abnormal behaviors recognized as a rodent schizophrenia model. The inhibitory effect was completely antagonized with nor-BNI (nor-binaltorphimine hydrochloride), a selective kappa opioid receptor antagonist. Second, TRK-820 dose-dependently inhibited phencyclidine-induced stereotyped behaviors including head-weaving, which is considered a behavioral syndrome based on the impairment of the serotonergic system. Third, in an in vivo microdialysis study, TRK-820 dose-dependently attenuated the biochemical changes of both dopamine and serotonin in the prefrontal cortex of rats treated with phencyclidine without affecting their basal levels in normal rats. The initial findings that TRK-820 potentially modulates such monoamine changes and ameliorates abnormal behaviors related to their changes may suggest its therapeutic potential against the symptoms of schizophrenia.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dopamine; Extracellular Space; Hyperkinesis; Male; Morphinans; Naltrexone; Phencyclidine; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Schizophrenia; Serotonin; Spiro Compounds