%0 Journal Article %A Vasco Meneghini %A Bruna Cuccurazzu %A Valeria Bortolotto %A Vera Ramazzotti %A Federica Ubezio %A Thomas M Tzschentke %A Pier Luigi Canonico %A Mariagrazia Grilli %T The Noradrenergic Component in Tapentadol Action Counteracts Mor-mediated Adverse Effects on Adult Neurogenesis %D 2014 %R 10.1124/mol.113.091520 %J Molecular Pharmacology %P mol.113.091520 %X Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippocampus. Literature data also suggest that norepinephrine (NE) is a positive modulator of hippocampal neurogenesis in vitro and in vivo. Based on these observations, we investigated whether tapentadol (TAP), a novel central analgesic combining mu opioid receptor (MOR) agonism with NE reuptake inhibition (NRI), may produce less inhibition of hippocampal neurogenesis compared to morphine. When tested in vitro, morphine inhibited neuronal differentiation, neurite outgrowth and survival of adult mouse hippocampal neural progenitors (NPC) and their progeny, via MOR interaction. In contrast, tapentadol was devoid of these adverse effects on cell survival and reduced neurite outgrowth and the number of newly generated neurons only at nM concentrations where the MOR component is predominant. On the contrary, at higher (μM) 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 proapototic 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, tapentadol combined mechanism of action may result in less or no reduction in adult neurogenesis compared to classical opiates. %U https://molpharm.aspetjournals.org/content/molpharm/early/2014/02/10/mol.113.091520.full.pdf