title: Relationship between serotonin transporter occupancies and analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine in reserpine-induced myalgia rats.
abstract: Serotonin (5-HT) and norepinephrine (NE) have been implicated in the mediation of endogenous analgesic mechanisms via the descending inhibitory pain pathway in the brain, and dysfunction in both the 5-HT and NE systems has been suggested as an etiology of fibromyalgia (FM). Given that 5-HT reuptake inhibition in the brain appears to be associated with pain reduction, this mechanism might exert an analgesic effect also on pain associated with FM. In this case, it would be of interest to investigate the correlation of 5-HT transporter (SERT) occupancy with in vivo analgesic effect on pain associated with FM. Here, we investigated the relationship between SERT occupancies and the analgesic effects of AS1069562, the (+)-isomer of indeloxazine, and duloxetine, which are both 5-HT and NE reuptake inhibitors (SNRIs), on muscular pain in reserpine-induced myalgia (RIM) rats, an animal model of FM-like chronic pain. We also investigated the SERT occupancy level necessary for AS1069562 and duloxetine to exert analgesic effects on muscular pain. AS1069562 and duloxetine attenuated muscular hyperalgesia in RIM rats, representing the first findings to be reported regarding the analgesic effect of AS1069562 on pain associated with FM. SERT occupancy levels of AS1069562 and duloxetine increased in both dose- and plasma and brain concentration-dependent manners. SERT occupancy levels of AS1069562 and duloxetine were significantly correlated with efficacy on muscular pain thresholds in RIM rats. This finding concerning the precise correlation of SERT occupancy with in vivo analgesic effect on pain associated with FM is reported here for the first time. SERT occupancy level above 70% was necessary for AS1069562 and duloxetine to exert significant analgesic effects on muscular pain. These results suggest that SERT occupancy level is useful in determining appropriate analgesic doses of AS1069562 and duloxetine for treating pain symptoms in FM patients.
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: nobuhito.murai@astellas.com.
authors.forename: N
authors.initials: N
authors.lastname: Murai
authors.affiliation: Bioimaging Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Fushiki
authors.affiliation: Bioimaging Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Honda
authors.affiliation: Bioimaging Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Bioimaging Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Iwashita
authors.affiliation: Analysis & Pharmacokinetics Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Irie
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tamura
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nagakura
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Aoki
mesh_terms: D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D059350:Chronic Pain / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride / Q000493:pharmacokinetics / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000493:pharmacokinetics / Q000494:pharmacology*; D063806:Myalgia / Q000188:drug therapy* / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects; D011312:Pressure; D017207:Rats, Sprague-Dawley; D012110:Reserpine; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; D009025:Morpholines; D050486:Serotonin Plasma Membrane Transport Proteins; C020852:indeloxazine; D012110:Reserpine; D000068736:Duloxetine Hydrochloride
keywords: AS1069562; duloxetine; fibromyalgia; occupancy; pain; serotonin transporter