title: Tapentadol increases levels of noradrenaline in the rat spinal cord as measured by in vivo microdialysis.
abstract: Spinal noradrenaline is thought to play an important role in descending pain inhibitory pathways and the modulation of nociceptive information at the spinal level. Tapentadol is a μ-opioid receptor (MOR) agonist and noradrenaline reuptake inhibitor (NRI). We showed previously that tapentadol, in contrast to morphine, elevates levels of noradrenaline, but not serotonin, in the ventral hippocampus of rats. The aim of this study was to examine the effects of tapentadol, morphine and venlafaxine on spinal monoamine levels. Rats were implanted with spinal microdialysis probes. Drugs were administered intraperitoneally, and samples were collected for 3h in isoflurane-anesthetized animals and analysed for monoamine content using HPLC-MS/MS. In terms of area-under-curve (AUC, 0-180 min), tapentadol (4.64-21.5mg/kg) produced a dose-dependent, significant increase in extracellular spinal noradrenaline levels (9275±4346 min% at the highest dose versus -1047±889 min% for vehicle). A maximum increase of 182±32% of baseline was reached 60 min after administration of 10mg/kg tapentadol. Venlafaxine (10mg/kg) produced an effect of similar magnitude. In contrast, tapentadol decreased extracellular spinal serotonin levels (non-significantly compared to vehicle), while venlafaxine increased spinal serotonin to 267±74% of baseline. In contrast to tapentadol and venlafaxine, morphine slightly decreased levels of noradrenaline and serotonin. This study demonstrates that analgesic doses of tapentadol (and venlafaxine), but not morphine, increase spinal noradrenaline levels and that tapentadol is devoid of a relevant serotonergic effect. It supports the suggestion that the NRI component of tapentadol is functionally relevant and contributes to its mechanism of action.
authors.affiliation: Global Preclinical Research and Development, Grünenthal Innovation, Grünenthal GmbH, Department of Pharmacology, Zieglerstrasse 6, 52078 Aachen, Germany. thomas.tzschentke@grunenthal.com
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Tzschentke
authors.forename: Joost H A
authors.initials: JH
authors.lastname: Folgering
authors.forename: Gunnar
authors.initials: G
authors.lastname: Flik
authors.forename: Jean
authors.initials: J
authors.lastname: De Vry
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D003511:Cyclohexanols / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009020:Morphine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology*; D012372:ROC Curve; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D000077432:Tapentadol; D000069470:Venlafaxine Hydrochloride
chemical_list: D000701:Analgesics, Opioid; D003511:Cyclohexanols; D010636:Phenols; D017450:Receptors, Opioid, mu; D009020:Morphine; D000069470:Venlafaxine Hydrochloride; D000077432:Tapentadol; D009638:Norepinephrine