title: The noradrenergic component in tapentadol action counteracts μ-opioid receptor-mediated adverse effects on adult neurogenesis.
abstract: Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippocampus. Literature data also suggest that norepinephrine is a positive modulator of hippocampal neurogenesis in vitro and in vivo. On the basis of these observations, we investigated whether tapentadol, a novel central analgesic combining μ-opioid receptor (MOR) agonism with norepinephrine reuptake inhibition (NRI), may produce less inhibition of hippocampal neurogenesis compared with morphine. When tested in vitro, morphine inhibited neuronal differentiation, neurite outgrowth, and survival of adult mouse hippocampal neural progenitors and their progeny, via MOR interaction. By contrast, tapentadol was devoid of these adverse effects on cell survival and reduced neurite outgrowth and the number of newly generated neurons only at nanomolar concentrations where the MOR component is predominant. On the contrary, at higher (micromolar) concentrations, tapentadol elicited proneurogenic and antiapoptotic effects via activation of β2 and α2 adrenergic receptors, respectively. Altogether, these data suggest that the noradrenergic component in tapentadol has the potential to counteract the adverse MOR-mediated effects on hippocampal neurogenesis. As a proof of concept, we showed that reboxetine, an NRI antidepressant, counteracted both antineurogenic and apoptotic effects of morphine in vitro. In line with these observations, chronic tapentadol treatment did not negatively affect hippocampal neurogenesis in vivo. In light of the increasing long-term use of opiates in chronic pain, in principle, the tapentadol combined mechanism of action may result in less or no reduction in adult neurogenesis compared with classic opiates.
authors: Laboratory of Neuroplasticity and Pain (V.M., B.C., V.B., V.R., F.U., M.G.) and Department of Pharmaceutical Sciences (V.M., B.C., V.B., V.R., F.U., P.L.C., M.G.), University of Eastern Piedmont Amedeo Avogadro, Novara, Italy; and Global Innovation, Department of Pain Pharmacology, Grünenthal GmbH, Aachen, Germany (T.M.T.).
authors: Vasco
authors: V
authors: Meneghini
authors: Bruna
authors: B
authors: Cuccurazzu
authors: Valeria
authors: V
authors: Bortolotto
authors: Vera
authors: V
authors: Ramazzotti
authors: Federica
authors: F
authors: Ubezio
authors: Thomas M
authors: TM
authors: Tzschentke
authors: Pier Luigi
authors: PL
authors: Canonico
authors: Mariagrazia
authors: M
authors: Grilli
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000502:physiology; D010636:Phenols / Q000494:pharmacology*; D011897:Random Allocation; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000502:physiology; D000077432:Tapentadol
chemical_list: D010636:Phenols; D017450:Receptors, Opioid, mu; D000077432:Tapentadol; D009638:Norepinephrine