title: μ-Opioid receptor activation and noradrenaline transport inhibition by tapentadol in rat single locus coeruleus neurons.
abstract: OBJECTIVE
  Tapentadol is a novel analgesic that combines moderate μ-opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule. Both mechanisms of action are involved in producing analgesia; however, the potency and efficacy of tapentadol in individual neurons has not been characterized.
  
  
  METHODS
  Whole-cell patch-clamp recordings of G-protein-coupled inwardly rectifying K(+) (KIR 3.x) currents were made from rat locus coeruleus neurons in brain slices to investigate the potency and relative efficacy of tapentadol and compare its intrinsic activity with other clinically used opioids.
  
  
  RESULTS
  Tapentadol showed agonist activity at μ receptors and was approximately six times less potent than morphine with respect to KIR 3.x current modulation. The intrinsic activity of tapentadol was lower than [Met]enkephalin, morphine and oxycodone, but higher than buprenorphine and pentazocine. Tapentadol inhibited the noradrenaline transporter (NAT) with potency similar to that at μ receptors. The interaction between these two mechanisms of action was additive in individual LC neurons.
  
  
  CONCLUSIONS
  Tapentadol displays similar potency for both µ receptor activation and NAT inhibition in functioning neurons. The intrinsic activity of tapentadol at the μ receptor lies between that of buprenorphine and oxycodone, potentially explaining the favourable profile of side effects, related to μ receptors.
  
  
  BACKGROUND
  This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
authors.affiliation: Discipline of Pharmacology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Sadeghi
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Tzschentke
authors.forename: MacDonald J
authors.initials: MJ
authors.lastname: Christie
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010636:Phenols / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000502:physiology; D000077432:Tapentadol
chemical_list: D000701:Analgesics, Opioid; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010636:Phenols; D017450:Receptors, Opioid, mu; D000077432:Tapentadol; D009638:Norepinephrine
keywords: GIRK channels; KIR3.x; locus coeruleus; noradrenalin reuptake inhibitor; opioid receptor agonist; tapentadol