title: Remifentanil produces cross-desensitization and tolerance with morphine on the mu-opioid receptor.
abstract: Remifentanil is a powerful mu-opioid (MOP) receptor agonist used in anaesthesia with a very short half-life. However, per-operative perfusion of remifentanil was shown to increase morphine consumption during post-operative period to relieve pain. In the present study, we aimed to describe the cellular mechanisms responsible for this apparent reduction of morphine efficacy. For this purpose, we first examined the pharmacological properties of both remifentanil and morphine at the MOP receptor, endogenously expressed in the human neuroblastoma SH-SY5Y cell line, to regulate adenylyl cyclase and the MAP kinase ERK1/2 pathway, their potency to promote MOP receptor phosphorylation, arrestin 3-CFP (cyan fluorescent protein) recruitment and receptor trafficking during acute and sustained exposure. In the second part of this work, we studied the effects of a prior exposure of remifentanil on morphine-induced inhibition of cAMP accumulation, activation of ERK1/2 and analgesia. We showed that sustained exposure to remifentanil promoted a rapid desensitization of opioid receptors on both signalling pathways and a pretreatment with this agonist reduced signal transduction produced by a second challenge with morphine. While both opioid agonists promoted Ser(375) phosphorylation on MOP receptor, remifentanil induced a rapid internalization of opioid receptors compared to morphine but without detectable arrestin 3-CFP translocation to the plasma membrane in our experimental conditions. Lastly, a cross-tolerance between remifentanil and morphine was observed in mice using the hot plate test. Our in vitro and in vivo data thus demonstrated that remifentanil produced a rapid desensitization and internalization of the MOP receptor that would reduce the anti-nociceptive effects of morphine.
authors.affiliation: Université de Caen, Laboratoire de signalisation, Électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, UPRES EA 4650, IFR 146 ICORE, Avenue côte de Nacre, 14032 Caen, France. nowoczyn_marie@yahoo.fr
authors.forename: M
authors.initials: M
authors.lastname: Nowoczyn
authors.forename: N
authors.initials: N
authors.lastname: Marie
authors.forename: L
authors.initials: L
authors.lastname: Coulbault
authors.forename: M
authors.initials: M
authors.lastname: Hervault
authors.forename: A
authors.initials: A
authors.lastname: Davis
authors.forename: J L
authors.initials: JL
authors.lastname: Hanouz
authors.forename: S
authors.initials: S
authors.lastname: Allouche
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004361:Drug Tolerance; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism; D000077208:Remifentanil
chemical_list: D000700:Analgesics; D019390:Arrestins; D010880:Piperidines; D017450:Receptors, Opioid, mu; C082333:arrestin3; D009020:Morphine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000077208:Remifentanil
keywords: Analgesia; CFP; DAMGO; DOP; Desensitization; ERK1/2; Extracellular-regulated kinase 1/2; G protein-coupled receptor; G protein-coupled receptor kinase; GFP; GPCR; GRK; MAP kinase; MOP; MPE; Mitogen-activated protein kinase; Morphine; Mu-opioid receptor; NTI; Remifentanil; Tolerance; [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin; cyan fluorescent protein; delta-opioid receptor; green fluorescent protein; maximal possible effect; mu-opioid receptor; naltrindole; β-funaltrexamine; βFNA