title: Occupancy of serotonin transporter by tramadol: a positron emission tomography study with [11C]DASB.
abstract: Tramadol is used for the treatment of pain, and it is generally believed to activate the μ-opioid receptor and inhibit serotonin (5-HT) and norepinephrine (NE) transporters. Recent findings from animal experiments suggest that 5-HT reuptake inhibition in brain is related to pain reduction. However, there has been no report of 5-HT transporter (5-HTT) occupancy by tramadol at clinical doses in humans. In the present study, we investigated 5-HTT occupancy by tramadol in five subjects receiving various doses of tramadol by using positron emission tomography (PET) scanning with the radioligand [11C]DASB. Our data showed that mean 5-HTT occupancies in the thalamus by single doses of tramadol were 34.7% at 50 mg and 50.2% at 100 mg. The estimated median effective dose (ED50) of tramadol was 98.1 mg, and the plasma concentration was 0.33 μg/ml 2 h after its administration; 5-HTT occupancy by tramadol was dose-dependent. We estimated 5-HTT occupancy at 78.7% upon taking an upper limit dose (400 mg) of tramadol. The results of the present study support the finding that 5-HTT inhibition is involved in the mechanism underlying the analgesic effect of tramadol in humans, and a clinical dose of tramadol sufficiently inhibits 5-HTT reuptake; this inhibition is similar to that shown by selective serotonin reuptake inhibitors (SSRIs).
authors.affiliation: Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.
authors.forename: Amane
authors.initials: A
authors.lastname: Tateno
authors.affiliation: Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Arakawa
authors.affiliation: Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakayori
authors.affiliation: Department of Pharmacology, Nippon Medical School, Tokyo, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Department of Pharmacology, Nippon Medical School, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Okubo
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000097:blood / Q000494:pharmacology*; D001596:Benzylamines; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013788:Thalamus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D014147:Tramadol / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D001596:Benzylamines; D002250:Carbon Radioisotopes; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; D019275:Radiopharmaceuticals; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D014147:Tramadol