Serotonin and Norepinephrine Transporter Occupancy of Tramadol in Nonhuman Primate Using Positron Emission Tomography

• Published in: The international journal of neuropsychopharmacology 2019-01, Vol.22 (1), p.53-56
• Main Authors: Arakawa, Ryosuke, Takano, Akihiro, Halldin, Christer
• Format: Article
• Language: English
• Subjects: Animals; Antidepressants; Antidepressive Agents - pharmacology; Benzylamines; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Brief Report; Diagnostic imaging; Dosage and administration; Dose-Response Relationship, Drug; Female; Health aspects; Macaca fascicularis; Male; Medicin och hälsovetenskap; Methods; Morpholines; Narcotics - pharmacology; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Occupancy; Phenols (Class of compounds); Positron emission tomography; Primates; Radiopharmaceuticals; Serotonin; Serotonin Plasma Membrane Transport Proteins - metabolism; Tomography; Tramadol; Tramadol - pharmacology
• ISSN: 1461-1457; 1469-5111; 1469-5111
• DOI: 10.1093/ijnp/pyy089

Tramadol, a centrally acting analgesic drug, has relatively high affinity to serotonin transporter and norepinephrine transporter in addition to μ-opioid receptor. Based on this characteristic, tramadol is expected to have an antidepressant effect. Positron emission tomography measurements with [11C]MADAM and [18F]FMeNER-D2 were performed at baseline and after i.v. administration of 3 different doses (1, 2, and 4 mg/kg) of tramadol using 6 cynomolgus monkeys. The relationship between dose and occupancy for serotonin transporter and norepinephrine transporter was estimated. Tramadol occupied similarly both serotonin transporter (40%-72%) and norepinephrine transporter (7%-73%) in a dose-dependent manner. The Kd was 2.2 mg/kg and 2.0 mg/kg for serotonin transporter and norepinephrine transporter, respectively. Both serotonin transporter and norepinephrine transporter of in vivo brain were blocked at >70% at a clinically relevant high dose of tramadol. This study suggests tramadol has potential antidepressant effects through the inhibition of serotonin transporter and norepinephrine transporter in the brain.