title: Effect of tapentadol on neurons in the locus coeruleus.
abstract: Tapentadol is a novel centrally acting drug that combines mu-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), producing analgesic effects in various painful conditions. We investigated the acute effects of tapentadol in the locus coeruleus (LC), a central nucleus regulated by the noradrenergic and opioid systems that is critical in pain modulation. In single-unit extracellular recordings of LC neurons from anaesthetized male Sprague-Dawley rats, tapentadol clearly inhibited the spontaneous electrophysiological activity of LC neurons in a dose-dependent manner (ED50 = 0.8 mg/kg). This inhibitory effect was reversed by RX821002 (an alpha2-adrenoceptor antagonist) and naloxone (a mu-opioid receptor antagonist) by 96.7% and 28.2%, respectively. Pretreatment with RX821002, N-ethoxycarbonyl-2-ethoxy-1-2-dihydroquinoline (EEDQ, an irreversible alpha2-adrenoceptor antagonist) or naloxone shifted the tapentadol dose-effect curve to the right (ED50 = 2.2 mg/kg, 2.0 mg/kg and 2.1 mg/kg, respectively). Furthermore, tapentadol inhibited the LC response to mechanical stimulation of the hindpaw in a dose-dependent manner. In summary, we demonstrate that acute administration of tapentadol inhibits LC neurons in vivo, mainly due to the activation of alpha2-adrenoceptors. These data suggest that both the noradrenergic and opioid systems participate in the inhibitory effect of tapentadol on LC neurons, albeit to different extents, which may account for its potent analgesic effect and mild opioidergic side-effects.
authors.affiliation: Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cadiz, 11003, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Torres-Sanchez
authors.forename: Cristina
authors.initials: C
authors.lastname: Alba-Delgado
authors.forename: Meritxell
authors.initials: M
authors.lastname: Llorca-Torralba
authors.forename: Juan A
authors.initials: JA
authors.lastname: Mico
authors.forename: Esther
authors.initials: E
authors.lastname: Berrocoso
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D008125:Locus Coeruleus / Q000166:cytology*; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077432:Tapentadol
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D010636:Phenols; D011804:Quinolines; C000470:EEDQ; C058525:2-methoxyidazoxan; D000077432:Tapentadol; D019329:Idazoxan