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Supplementary Table 1. Pharmacological manipulation of the Diffuse Noxious Inhibitory Controls circuitry. Listed by year and first author. DNIC EXPRESSION BEFORE DNIC EXPRESSION AFTER PMID FIRST AUTHOR YEAR ANIMAL CONDITION DRUG INJECTION SITE DOSE ANAESTH. READOUT TESTING STIMULUS COND. STIMULUS READOUT PLACE TARGETED SYSTEM COMMENT DRUG DRUG Thermal Rat P-chlorophenylalanine: Irreversible inhibitor of 6454457 Dickenson AH 1981 Naïve P-chlorophenylalanine Systemic (i.p.) 300 mg/kg/day (3 days) Halothane Eph Electrical Mechanical Spinal WDR Executive system Expressed Not expressed (♂, SD) tryptophan hydroxylase (serotonin depletion) Chemical 0.01 mg/kg 0.1 mg/kg Morphine Systemic (i.v.) Systemic Expressed Not expressed 1 mg/kg Morphine: μ-opioid receptor agonist (MOR) Rat 2 mg/kg Thermal 7260590 Le Bars D 1981 Naïve Halothane Eph Electrical Spinal WDR (♂, SD) Mechanical Naloxone: Opioid receptor antagonist 0.1-0.2 mg/kg Naloxone Systemic (i.v.) Systemic Expressed Expressed 0.3-0.4 mg/kg 40 μg/kg Rat 6260285 Kraus E 1981 Naïve Naloxone Systemic (i.v.) 100 μg/kg N/A Beh Electrical Chemical Vocalization Systemic Expressed Not expressed Naloxone: Opioid receptor antagonist (♂, SD) 200 μg/kg Rat 6257327 Le Bars D 1981 Naïve Naloxone Systemic (i.v.) 0.3 mg/kg Halothane Eph Electrical Thermal Spinal WDR Systemic Expressed Not expressed Naloxone: Opioid receptor antagonist (♂, SD) Cinanserin Systemic (i.v.) 4 mg/kg Systemic Expressed Not expressed Cinanserin: 5-HT2A and 5-HT2C receptor antagonist Rat Thermal 6978166 Chitour D 1982 Naïve Metergoline Systemic (i.v.) 5 mg/kg Halothane Eph Electrical Spinal WDR Systemic Expressed Not expressed Metergoline: 5-HT1, 5-HT2 and 5-HT7 receptor (♂, SD) Mechanical antagonist 5-hydroxytryptophan Systemic (i.v.) 35 mg/kg Systemic Expressed Expressed (enhanced) 5-hydroxytryptophan: Serotonin precursor 5.55 mg/kg 5-hydroxytryptophan Systemic (i.p.) 16.6 mg/kg Systemic Expressed Expressed (enhanced) 50 mg/kg 5-hydroxytryptophan: Serotonin precursor Rat 6976820 Kraus E 1982 Naïve N/A Beh Electrical Chemical Vocalization (♂, SD) Cinanserin Systemic (i.p.) 10 mg/kg Systemic Expressed Expressed (enhanced) Cinanserin: 5-HT2A and 5-HT2C receptor antagonist 5-hydroxytryptophan + Systemic (i.p.) 50 mg/kg + 10 mg/kg Systemic Expressed Expressed Cinanserin Rat Xylocaine Thermal Descending system 6626970 Cadden SW 1983 Naïve Infusion (C2) 25μl (5%) Halothane Eph Mechanical Spinal WDR Expressed Not expressed Lidocaine: Voltage-gated sodium channel blocker (♂, SD) (lidocaine) Mechanical (NO TABLE) Rat Microinjection medioventral 6664236 Dickenson AH 1983 Naïve Morphine 5μg in 0.2μl Halothane Eph Electrical Thermal Spinal WDR Top-down system Expressed Not expressed Morphine: μ-opioid receptor agonist (MOR) (♂, ??) periaqueductal grey (PAG) Rat ES 52: Inhibitor of enkephalinase (derivative of 2986769 Villanueva L 1985 Naïve ES 52 Systemic (i.v.) 10 mg/kg Halothane Eph Electrical Thermal Spinal WDR Systemic Expressed Expressed (♂, SD) Thiorphan) Expressed (paw) Morphine sulfate Intrathecal (i.th.) 15μg in 20μl Ascending TS or CS Expressed Morphine: μ-opioid receptor agonist (MOR) Rat 3763236 Villanueva L 1986 Naïve Halothane Eph Electrical Thermal Medullary WDR Not expressed (tail) (♂, ??) Naloxone: Opioid receptor antagonist Naloxone Systemic (i.v.) 0.4 mg/kg Ascending TS or CS Expressed Expressed 0μg in 2μl 0.6μg in 2μl Intracerebroventricular 1.25μg in 2μl Morphine sulphate Systemic Expressed Not expressed (i.c.v.) 2.5μg in 2μl Morphine: μ-opioid receptor agonist (MOR) Rat 3171978 Bouhassira D 1988 Naïve 10μg in 2μl Halothane Eph Electrical Thermal Spinal WDR (♂, SD) 40μg in 2μl Naloxone: Opioid receptor antagonist Naloxone Systemic (i.v.) 0.4 mg/kg Systemic Expressed Expressed Intracerebroventricular Morphine base 10μg in 2μl Systemic Expressed Not expressed (i.c.v.) Morphine: μ-opioid receptor agonist (MOR) Rat 3378576 Bouhassira D 1988 Naïve Halothane Eph Mechanical Thermal Spinal WDR (♂, SD) Naloxone: Opioid receptor antagonist Naloxone Systemic (i.v.) 0.4 mg/kg Systemic Expressed Expressed Rat Thermal 2247225 Bing Z 1990 Naïve Naloxone Systemic (i.v.) 0.4 mg/kg Halothane Eph Electrical Medullary WDR Systemic Expressed Not expressed Naloxone: Opioid receptor antagonist (♂, SD) Mechanical Morphine chlorhydrate 1 mg/kg Expressed Not expressed Naïve Systemic (i.v.) Systemic Morphine: μ-opioid receptor agonist (MOR) Rat Naloxone 0.4 mg/kg Expressed Not expressed 1397003 Bouhassira D 1992 Halothane Eph Electrical Thermal Spinal WDR (♂, SD) Naloxone: Opioid receptor antagonist Periaqueductal grey Morphine chlorhydrate Systemic (i.v.) 1 mg/kg Systemic Expressed Expressed (PAG) lesion 0.3 μg/kg Rat Buprenorphine 1 μg/kg Buprenorphine: Partial μ-opioid receptor (MOR) 8750730 Guirimand F 1995 Naïve Systemic (i.v.) Halothane EMG Electrical Thermal Biceps femoris muscle Systemic Expressed Not expressed (??, SD) hydrochloride 2 μg/kg agonist 3 μg/kg Rat Thermal 8973815 Okada K 1996 Naïve Capsaicin Sciatic nerve (cotton ball) 1.5% Thiamylal sodium EMG Electrical Jaw-opening reflex (JOR) Ascending TS or CS Expressed Not expressed Capsaicin: TRPV1 agonist (??, W) Mechanical Rat Microinjection nucleus raphe 2.5μg in 0.25μl 9729390 Dualé C 1998 Naïve Morphine hydrochloride Halothane Eph Electrical Thermal Medullary WDR Top-down system Expressed Expressed Morphine: μ-opioid receptor agonist (MOR) (♂, SD) magnus (RMg) 5μg in 0.5μl Isoflurane: General anaesthetic Expressed (0.8 MAC) 0.8 MAC Rat 12818952 Jinks SL 2003 Naïve Isoflurane Gaseous (inhaled) 1.2 MAC Isoflurane Eph Thermal Mechanical Spinal WDR Systemic Expressed MAC: Minimum alveolar anaesthetic (♂, SD) (MAC = 1.2% ± 0.1%) concentration necessary to produce immobility Not expressed (1.2 MAC) to a noxious stimulus Dexmedetomidine 3 μg/kg/hr (5 min) Systemic (i.v.) Systemic Expressed Not expressed hydrochloride 0.5 μg/kg/hr until end Dexmedetomidine: α2-adrenoceptor agonist Phenylephrine: α1-adrenoceptor agonist Phenylephrine Systemic (i.v.) 5 μg/kg/min (10 min) Systemic Expressed Not expressed Rat 19697515 Sanada T 2009 Naïve Sevoflurane EMG Electrical Thermal Biceps femoris muscle (♂, W) Atipamezole: α2-adrenoceptor antagonist Atipamezole hydrochloride Systemic (i.m.) 0.5 mg/kg Systemic Expressed Expressed Phentolamine mesylate: α1/2-adrenoceptor antagonist Phentolamine mesylate Systemic (i.m.) 0.1 mg/kg Systemic Expressed Expressed NOT STATED RP67581 Intrathecal (i.th.) Ascending TS or CS Expressed Expressed (probably 20μg in 10μl) N/A Beh Chemical Chemical Facial grooming RP67581: NK1R inactive antagonist Rat 19231081 Lapirot O 2009 Naïve RP67580 Intrathecal (i.th.) 20μg in 10μl Ascending TS or CS Expressed Not expressed RP67580: NK1R antagonist (♂, SD) Muscimol: Neurotoxin, GABA-A agonist Microinjection left Muscimol 0.25nmol in 100nl Halothane Eph Electrical Thermal Medullary WDR Ascending TS or CS Expressed Not expressed parabrachial area (PB) Subcutaneous pellets 75mg (x2) Systemic Expressed Morphine sulfate Not expressed Subcutaneous osmotic 1 μl/h (64 mg/ml) Systemic Expressed Morphine: μ-opioid receptor agonist (MOR) Rat minipumps 20016098 Okada-Ogawa A 2009 Naïve Urethane Eph Thermal Thermal (fast and slow) Spinal WDR (♂, SD) Lidocaine: Voltage-gated sodium channel blocker Microinjection rostral Lidocaine 500nl (4%) Top-down system Expressed Expressed ventromedial medulla (RVM) Expressed (elect.) Naloxone Systemic (i.p.) 2 mg/kg + 1 mg/kg Systemic Expressed Yohimbine: α2-adrenoceptor antagonist Rat Electrical 20302612 Wen YR 2010 Naïve Halothane Beh Thermal Tail flick latency (TFL) Not expressed (chem.) (♂, SD) Chemical Naloxone: Opioid receptor antagonist Yohimbine Intrathecal (i.th.) 30μg in 20μl Executive system Expressed Not expressed Rat Microinjection nucleus raphe 20357157 Makino K 2010 Naïve Phenylephrine 0.05μg in 0.05μl Sevoflurane EMG Electrical Thermal Biceps femoris muscle Top-down system Expressed Not expressed Phenylephrine: α1-adrenoceptor agonist (♂, SD) magnus (RMg) Rat Microinjection medullary 21514054 Lapirot O 2011 Naïve Sulpiride 5nmol in 0.25μl Halothane Eph Electrical Thermal Medullary WDR Executive system Expressed Not expressed Sulpiride: Dopamine receptor 2 antagonist (♂, SD) dorsal horn (MDH) Systemic (s.c.) 3 mg/kg Systemic Expressed Not expressed Microinjection rostral 20μg in 0.5μl Top-down system Expressed Expressed Rat Muscle inflammation ventromedial medulla (RVM) 21330219 de Resende MA 2011 Naloxone N/A Beh Mechanical Thermal Paw withdrawal Naloxone: Opioid receptor antagonist (♂, SD) by carrageenan Microinjection medullary reticularis nucleus dorsalis 20μg in 0.5μl (per side) Top-down system Expressed Not expressed (MdD) Rat 21929659 Robbins A 2012 Naïve Morphine sulfate Subcutaneous pellets 75mg (x2) Urethane IHC Thermal Thermal Medullary WDR Systemic Expressed Not expressed Morphine: μ-opioid receptor agonist (MOR) (♂, SD) DAMGO-enkephalin Intrathecal (i.th.) 5μg in 10μl Ascending TS or CS Expressed Not expressed DAMGO: μ-opioid and δ-opioid receptor agonist (MOR-DOR) Naloxone Systemic (i.v.) 0.4 mg/kg Systemic Expressed Expressed Rat Thermal Deltorphin II: δ-opioid receptor agonist (DOR) 23843537 Normandin A 2013 Naïve Halothane Eph Electrical Medullary WDR (♂, SD) Mechanical Deltorphin II Intrathecal (i.th.) 8μg in 10μl Ascending TS or CS Expressed Not expressed Naloxone: Opioid receptor antagonist Naltrindole: δ-opioid receptor antagonist (DOR) Naltrindole Systemic (i.v.) 4 mg/kg Systemic Expressed Expressed Microinjection nucleus raphe 0.25nmol in 100nl Muscimol Top-down system Expressed Not expressed magnus (NRM)
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  • Opioid-Induced Inhibition of the Human 5-HT and Noradrenaline Transporters in Vitro: Link to Clinical Reports of Serotonin Syndrome

    Opioid-Induced Inhibition of the Human 5-HT and Noradrenaline Transporters in Vitro: Link to Clinical Reports of Serotonin Syndrome

    British Journal of British Journal of Pharmacology (2018) 175 532–543 532 BJP Pharmacology RESEARCH PAPER Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome Correspondence Professor Matthias E. Liechti, Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Schanzenstrasse 55, Basel, CH-4056, Basel, Switzerland. E-mail: [email protected] Received 21 June 2017; Revised 3 November 2017; Accepted 8 November 2017 Anna Rickli1, Evangelia Liakoni2, Marius C Hoener3 and Matthias E Liechti1 1Clinical Pharmacology and Toxicology, Department of Biomedicine, Department of Internal Medicine, University Hospital Basel, University of Basel, Basel, Switzerland, 2Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, Univer- sity of Bern, Bern, Switzerland, and 3Neuroscience Research, pRED, Roche Innovation Center Basel, F.Hoffmann-La Roche Ltd, Basel, Switzerland BACKGROUND AND PURPOSE Opioids may inhibit the 5-HT transporter (SERT) and the noradrenaline transporter (NET). NET inhibition may contribute to an- algesia, and SERT inhibition or interactions with 5-HT receptors may cause serotonergic toxicity. However, the effects of different opioids on the human SERT, NET and 5-HT receptors have not been sufficiently studied. EXPERIMENTAL APPROACH We determined the potencies of different opioids to inhibit the SERT and NET in vitro using human transporter-transfected fi HEK293 cells. We also tested binding af nities at 5-HT1A,5-HT2A and 5-HT2C receptors. Additionally, we assessed clinical cases of the serotonin syndrome associated with each opioid reported by PubMed and a World Health Organization database. KEY RESULTS Dextromethorphan, l(R)-methadone, racemic methadone, pethidine, tramadol and tapentadol inhibited the SERT at or close to observed drug plasma or estimated brain concentrations in patients.