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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 Systemic (i.v.) Systemic Expressed Not expressed 1 mg/kg Morphine: μ- receptor (MOR) Rat 2 mg/kg Thermal 7260590 Le Bars D 1981 Naïve Halothane Eph Electrical Spinal WDR (♂, SD) Mechanical : 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 : Voltage-gated sodium (♂, 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 (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) )

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 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 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

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- 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 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) 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) 0.75nmol in 300nl Muscimol: Neurotoxin, GABA-A agonist Rat 24681000 Chebbi R 2014 Naïve Halothane Eph Electrical Thermal Medullary WDR (♂, SD) Kynurenate: Excitatory amino acid receptor Microinjection nucleus raphe antagonist Kynurenate 1nmol in 200nl Top-down system Expressed Expressed magnus (NRM)

Atipamezole Topically in the spinal cord 100μg in 50μl Executive system Expressed Not expressed Atipamezole: α2-adrenoceptor antagonist Naïve

Yohimbine Systemic (s.c.) 5 mg/kg Systemic Expressed Not expressed Yohimbine: α2-adrenoceptor antagonist

Ondansetron: 5-HT3 receptor antagonist Rat 26010460 Bannister K 2015 Ondansetron Topically in the spinal cord 100μg in 50μl Isoflurane Eph Mechanical Mechanical Spinal WDR Executive system Not expressed Expressed (♂, SD) : Norepinephrine reuptake inhibitor (NRI) Spinal nerve ligation Reboxetine mesylate Topically in the spinal cord 100μg in 50μl Executive system Not expressed Expressed (SNL) : Norepinephrine reuptake inhibitor (NRI) and μ-opioid receptor (MOR) agonist Tapentadol Systemic (s.c.) 1 mg/kg Systemic Not expressed Expressed

Systemic (i.p.) 3 mg/kg in 10μl Systemic Expressed

Naloxone Not expressed Intracerebroventricular Naloxone: Opioid receptor antagonist 10 μg in 10μl Systemic Expressed (i.c.v.) Rat Mechanical 27178898 Itomi Y 2016 Naïve N/A Beh Chemical Paw withdrawal Yohimbine: α2-adrenoceptor antagonist (♂, SD) Electrical

Yohimbine Intrathecal (i.th.) 30 μg in 10μl Executive system Expressed Not expressed WAY-100635: 5-HT1A receptor antagonist

WAY-100635 Intrathecal (i.th.) 3 μg in 10μl Executive system Expressed Not expressed

Rat Dural stimulation with : Non-selective β-adrenoceptor 28700539 Boyer N 2017 Propranolol Oral gavage 10 mg/kg/day (8 days) Halothane Eph Electrical Thermal Medullary WDR Systemic Not expressed Expressed (♂, SD) inflammatory soup (IS) antagonist

Spinal cord (topically) 100μg in 50μl Executive system Not expressed Expressed

Systemic (s.c.) 10 mg/kg Systemic Not expressed Not expressed

Citalopram + Spinal cord (topically) 100μg + 100μg in 50μl Executive system Not expressed Not expressed Atipamezole Citalopram: Selective serotonin reuptake inhibitor (SSRI)

Citalopram + SB269970 Spinal cord (topically) 100μg + 100μg in 50μl Executive system Not expressed Not expressed : Selective serotonin Rat Spinal nerve ligation 27891703 Bannister K 2017 Isoflurane Eph Mechanical Mechanical Spinal WDR reuptake inhibitor (SSRI) (♂, SD) (SNL) Spinal cord (topically) 100μg in 50μl Executive system Not expressed Expressed Atipamezole: α2-adrenoceptor antagonist Fluoxetine SB269970: 5-HT7 receptor antagonist Systemic (s.c.) 20 mg/kg Systemic Not expressed Not expressed

Fluoxetine + Spinal cord (topically) 100μg + 100μg in 50μl Executive system Not expressed Not expressed Atipamezole

Fluoxetine + SB269970 Spinal cord (topically) 100μg + 100μg in 50μl Executive system Not expressed Not expressed

Subcutaneous osmotic 7.68 mg/kg/day (7 days) Naïve Morphine sulfate (priming) Systemic Expressed Expressed minipumps (priming)

Subcutaneous osmotic 7.68 mg/kg/day (7 days) Morphine sulfate (priming) Systemic Expressed Not expressed minipumps (priming)

Minipump (priming) + Priming + Systemic Not expressed Expressed Systemic (s.c.) 3 mg/kg

Morphine: μ-opioid receptor agonist (MOR) Rat Minipump (priming) + 29369967 Nation K 2018 N/A Beh Mechanical Chemical Paw withdrawal (♂, SD) Microinjection right central Top-down system Not expressed Expressed Nor-: Kappa opioid receptor Environmental bright amygdala (RCeA) antagonist (KOR) light stress (BLS) Priming + Morphine sulfate (priming) 2.5 μg in 0.5 μl (per site) + Minipump (priming) + Nor-binaltorphimine Microinjection left central Top-down system Not expressed Not expressed amygdala (LCeA)

Minipump (priming) + Priming + Microinjection rostral Top-down system Not expressed Not expressed 2.5 μg in 0.5 μl (per site) ventromedial medulla (RVM)

Systemic (s.c.) 3 mg/kg Systemic Not expressed Expressed

N/A Beh Mechanical Chemical Paw withdrawal Microinjection right central Rat Spinal nerve ligation 2.5 μg in 0.5 μl Top-down system Nor-binaltorphimine: Kappa opioid receptor 30870321 Phelps C 2019 Nor-binaltorphimine amygdala (RCeA) (♂, SD) (SNL) antagonist (KOR) Not expressed Expressed

Microinjection right central 2.5 μg in 0.5 μl Isoflurane Eph Mechanical Mechanical Spinal WDR Top-down system amygdala (RCeA)

1 mg/kg Tapentadol Systemic (s.c.) 2 mg/kg Systemic Not expressed Expressed 5 mg/kg Tapentadol: Norepinephrine reuptake inhibitor (NRI) and μ-opioid receptor (MOR) agonist Rat Osteoarthritis (OA) by 30821870 Lockwood S 2019 Isoflurane Eph Mechanical Mechanical Spinal WDR (♂, SD) MIA (late stage) Systemic (s.c.) 10 mg/kg Systemic Not expressed Not expressed Pregabalin: Blocker of voltage-gated calcium channels (VGCCs) that inhibits neurotransmitter release 1 mg/kg + 10 mg/kg Tapentadol + Pregabalin Systemic (s.c.) Systemic Not expressed Expressed 2 mg/kg + 5 mg/kg

SB269970 Spinal cord (topically) 100 μg in 50 μl Executive system Expressed Not expressed Osteoarthritis (OA) by SB269970: 5-HT7 receptor antagonist MIA (early stage) Atipamezole Spinal cord (topically) 100 μg in 50 μl Executive system Expressed Not expressed Atipamezole: α2-adrenoceptor antagonist Rat 30461363 Lockwood S 2019 Isoflurane Eph Mechanical Mechanical Spinal WDR (♂, SD) Tapentadol: Norepinephrine reuptake inhibitor Tapentadol Systemic (s.c.) 2 mg/kg Systemic Not expressed Expressed (NRI) and μ-opioid receptor (MOR) agonist Osteoarthritis (OA) by MIA (late stage) AS-19: 5-HT7 receptor agonist AS-19 Spinal cord (topically) 100 μg in 50 μl Executive system Not expressed Expressed

Sumatriptan succinate 0.6 mg/kg/day (7 days) Systemic Expressed Not expressed (priming) 3 mg/kg/day (7 days) Sumatriptan: 5-HT1 receptor agonist Rat Subcutaneous osmotic 30286616 Nation K 2019 Naïve N/A Beh Mechanical Chemical Paw withdrawal (♂, SD) minipumps Morphine: μ-opioid receptor agonist (MOR) Morphine sulfate (priming) 7.68 mg/kg/day (7 days) Systemic Expressed Not expressed

Naïve Yohimbine Intrathecal (i.t.) 100 μg in 10 μl Executive system Expressed Not expressed

Duloxetine Systemic (s.c.) 10 mg/kg Systemic Not expressed Expressed Yohimbine: α2-adrenoceptor antagonist Partial sciatic nerve Pregabalin Orally administered (p.o.) 10 mg/kg Systemic Not expressed Not expressed ligation (PSNL) : Serotonin and noradrenergic reuptake inhibitor (SNRI) Rat 32315711 Yoneda S 2020 Orally administered (p.o.) 3 mg/kg N/A Beh Mechanical Chemical Paw withdrawal Systemic Not expressed Not expressed (♂, SD) Pregabalin: Blobcker of voltage-gated calcium channels (VGCCs) that inhibits neurotransmitter release Duloxetine Systemic (s.c.) 10 mg/kg Systemic Not expressed Expressed Celecoxib: Cyclooxygenase 2 inhibitor (COX-2) Osteoarthritis (OA) by Pregabalin Orally administered (p.o.) 10 mg/kg Systemic Not expressed Not expressed MIA (late stage)

Celecoxib Orally administered (p.o.) 3 mg/kg Systemic Not expressed Not expressed

Rat Spinal nerve ligation Microinjection right central 31725062 Navratilova E 2020 Morphine sulfate 1 μg in 0.2 μl N/A Beh Mechanical Chemical Paw withdrawal Top-down system Not expressed Expressed Morphine: μ-opioid receptor agonist (MOR) (♂, SD) (SNL) amygdala (RCeA)

Microinjection dorsal Naloxone hydrochloride 5 μg in 0.5 μl Top-down system Expressed Not expressed reticular nucleus (DRt) Naïve

Microinjection infralimbic Lidocaine 0.5 μl (2% w/v) Top-down system Expressed Not expressed region (ILC) Naloxone: Opioid receptor antagonist Rat 31518451 Patel R 2020 Isoflurane Eph Mechanical Mechanical Spinal WDR (♂, SD) Lidocaine: Voltage-gated sodium channel blocker Microinjection dorsal Naloxone hydrochloride 5 μg in 0.5 μl Top-down system Not expressed Not expressed reticular nucleus (DRt) Spinal nerve ligation (SNL) Microinjection infralimbic Lidocaine 0.5 μl (2% w/v) Top-down system Not expressed Expressed region (ILC)

Antidopamine beta- Microinjection left lateral 5 μg in 5 μl Systemic Expressed Not expressed hydroxylase saporin ventricle Naïve

Atipamezole hydrochloride Systemic (s.c.) 1 mg/kg Systemic Expressed Not expressed Antidopamine beta-hydroxylase saporin: Neurotoxin, ablates noradrenergic neurons

Reboxetine mesylate Systemic (i.p.) 40 mg/kg/day (3 days) Systemic Not expressed Not expressed Atipamezole: α2-adrenoceptor antagonist

Reboxetine: Norepinephrine reuptake inhibitor 5,7-dihydroxytryptamine + Intrathecal (i.t.) + Systemic (NRI) 60 μg in 20 μl + 30 mg/kg Systemic Not expressed Not expressed hydrochloride (i.p.) 5,7-dihydroxytryptamine: Neurotoxin, depletes Rat 32745472 Irvine K 2020 N/A Beh Mechanical Chemical Paw withdrawal serotonergic fibers (♂, SD) Duloxetine hydrochloride Systemic (s.c.) 10 mg/kg/day (3 days) Systemic Not expressed Expressed Desipramine: (TCA) Traumatic brain injury noradrenaline reuptake inhibitor (NRI) (TBI) by LFP hydrochloride Systemic (s.c.) 10 mg/kg/day (3 days) Systemic Not expressed Expressed Duloxetine: Serotonin and noradrenergic reuptake inhibitor (SNRI) Systemic (i.p.) + Systemic 10 mg/kg/day (3 days) + Escitalopram + Atipamezole Systemic Not expressed Expressed (s.c.) 1 mg/kg Escitalopram: Selective serotonin reuptake inhibitor (SSRI)

5,7-dihydroxytryptamine + Systemic (i.t.) + Systemic 60 μg in 20 μl + 30 mg/kg + Desipramine + Systemic Not expressed Not expressed (i.p.) 10 mg/kg/day (3 days) Escitalopram

Supplementary Table 2. DNIC expression after systemic drug application. Listed by the drug.

DNIC EXPRESSION DNIC EXPRESSION PMID CONDITION DRUG INJECTION SITE ANAESTHESIA READOUT PHARMACOLOGY BEFORE DRUG AFTER DRUG

6260285 Naïve Naloxone Systemic (i.v.) N/A Beh Expressed Not expressed Opioid receptor antagonist

6257327 Naïve Naloxone Systemic (i.v.) Halothane Eph Expressed Not expressed Opioid receptor antagonist

2247225 Naïve Naloxone Systemic (i.v.) Halothane Eph Expressed Not expressed Opioid receptor antagonist

27178898 Naïve Naloxone Systemic (i.p.) N/A Beh Expressed Not expressed Opioid receptor antagonist

20302612 Naïve Naloxone Systemic (i.p.) Halothane Beh Expressed Not expressed Opioid receptor antagonist

Muscle 21330219 Naloxone Systemic (s.c.) N/A Beh Expressed Not expressed Opioid receptor antagonist inflammation

Intracerebroventricula 27178898 Naïve Naloxone N/A Beh Expressed Not expressed Opioid receptor antagonist r (i.c.v.)

Systemic (i.v.) + MOR-DOR agonist + opioid 7260590 Naïve Morphine + Naloxone Halothane Eph Expressed Expressed Systemic (i.v.) receptor antagonist

MOR-DOR agonist + opioid 3171978 Naïve Morphine + Naloxone i.c.v.. + Systemic (i.v.) Halothane Eph Expressed Expressed receptor antagonist

MOR-DOR agonist + opioid 3378576 Naïve Morphine + Naloxone i.c.v.. + Systemic (i.v.) Halothane Eph Expressed Expressed receptor antagonist

Systemic (i.v.) + MOR-DOR agonist + opioid 1397003 Naïve Morphine + Naloxone Halothane Eph Expressed Expressed Systemic (i.v.) receptor antagonist

Opioid receptor antagonist + MOR 23843537 Naïve Naloxone + DAMGO Systemic (i.v.) + i.th. Halothane Eph Expressed Expressed agonist

Naltrindole + 23843537 Naïve Systemic (i.v.) + i.th. Halothane Eph Expressed Expressed DOR antagonist + DOR agonist Deltorphin II

7260590 Naïve Morphine Systemic (i.v.) Halothane Eph Expressed Not expressed MOR-DOR agonist

1397003 Naïve Morphine Systemic (i.v.) Halothane Eph Expressed Not expressed MOR-DOR agonist

1397003 PAG lesion Morphine Systemic (i.v.) Halothane Eph Expressed Expressed MOR-DOR agonist

20016098 Naïve Morphine sulfate Subcutaneous pellets Urethane Eph Expressed Not expressed MOR-DOR agonist

Subcutaneous 20016098 Naïve Morphine sulfate Urethane Eph Expressed Not expressed MOR-DOR agonist osmotic minipumps

21929659 Naïve Morphine sulfate Subcutaneous pellets Urethane IHC Expressed Not expressed MOR-DOR agonist

Subcutaneous 29369967 Naïve Morphine sulfate N/A Beh Expressed Expressed MOR-DOR agonist osmotic minipumps

Subcutaneous 30286616 Naïve Morphine sulfate N/A Beh Expressed Not expressed MOR-DOR agonist osmotic minipumps

Intracerebroventricula 3171978 Naïve Morphine sulphate Halothane Eph Expressed Not expressed MOR-DOR agonist r (i.c.v.)

Intracerebroventricula 3378576 Naïve Morphine base Halothane Eph Expressed Not expressed MOR-DOR agonist r (i.c.v.)

29369967 BLS nor-binaltorphimine Systemic (s.c.) N/A Beh Not expressed Expressed MOR agonist

30870321 SNL Nor-binaltorphimine Systemic (s.c.) N/A Beh Not expressed Expressed KOR antagonist

Inhibitor of enkephalinase 2986769 Naïve ES 52 Systemic (i.v.) Halothane Eph Expressed Expressed (derivative of Thiorphan)

Buprenorphine 8750730 Naïve Systemic (i.v.) Halothane EMG Expressed Not expressed Partial MOR agonist hydrochloride

26010460 SNL Tapentadol Systemic (s.c.) Isoflurane Eph Not expressed Expressed NRI and MOR agonist

OA-MIA (late 30821870 Tapentadol Systemic (s.c.) Isoflurane Eph Not expressed Expressed NRI and MOR agonist stage)

OA-MIA (late 30461363 Tapentadol Systemic (s.c.) Isoflurane Eph Not expressed Expressed NRI and MOR agonist stage)

OA-MIA (late Tapentadol + NRI and MOR agonist + 30821870 Systemic (s.c.) Isoflurane Eph Not expressed Expressed stage) Pregabalin See below

OA-MIA (late 30821870 Pregabalin Systemic (s.c.) Isoflurane Eph Not expressed Not expressed stage)

Blocker of voltage-gated calcium Orally administered 32315711 PSNL Pregabalin N/A Beh Not expressed Not expressed channels (VGCCs) that inhibits (p.o.) neurotransmitter release

OA-MIA (late Orally administered 32315711 Pregabalin N/A Beh Not expressed Not expressed stage) (p.o.)

26010460 SNL Yohimbine Systemic (s.c.) Isoflurane Eph Not expressed Not expressed α2-adrenoceptor antagonist

Atipamezole 32745472 Naïve Systemic (s.c.) N/A Beh Expressed Not expressed α -adrenoceptor antagonist hydrochloride 2

Atipamezole hydrochloride + Systemic (i.m.) + α -adrenoceptor antagonist + α - 19697515 Naïve Sevoflurane EMG Expressed Expressed 2 2 Dexmedetomidine Systemic (i.v.) adrenoceptor agonist hydrochloride

Phentolamine Contralateral biceps α -adrenoceptor antagonist + α - 19697515 Naïve mesylate + Sevoflurane EMG Expressed Expressed 1/2 1 femoris (i.m.) adrenoceptor agonist Phenylephrine

Non-selective β-adrenoceptor 28700539 Migraine model Propranolol Oral gavage Halothane Eph Not expressed Expressed antagonist

Dexmedetomidine 19697515 Naïve Systemic (i.v.) Sevoflurane EMG Expressed Not expressed α -adrenoceptor agonist hydrochloride 2

19697515 Naïve Phenylephrine Systemic (i.v.) Sevoflurane EMG Expressed Not expressed α1-adrenoceptor agonist

5-HT , 5-HT and 5-HT receptor 6978166 Naïve Metergoline Systemic (i.v.) Halothane Eph Expressed Not expressed 1 2 7 antagonist

5-HT and 5-HT receptor 6976820 Naïve Cinanserin Systemic (i.p.) N/A Beh Expressed Expressed 2A 2C antagonist

5-HT and 5-HT receptor 6978166 Naïve Cinanserin Systemic (i.v.) Halothane Eph Expressed Not expressed 2A 2C antagonist

5-hydroxytryptophan + Serotonin precursor + 5-HT2A and 5- 6976820 Naïve Systemic (i.p.) N/A Beh Expressed Expressed cinanserin HT2C receptor antagonist

6978166 Naïve 5-hydroxytryptophan Systemic (i.v.) Halothane Eph Expressed Expressed Serotonin precursor

6976820 Naïve 5-hydroxytryptophan Systemic (i.p.) N/A Beh Expressed Expressed Serotonin precursor

27891703 SNL Citalopram Systemic (s.c.) Isoflurane Eph Not expressed Not expressed SSRI

27891703 SNL Fluoxetine Systemic (s.c.) Isoflurane Eph Not expressed Not expressed SSRI

OA MIA (late 32315711 Duloxetine Systemic (s.c.) N/A Beh Not expressed Expressed SNRI stage)

32315711 PSNL Duloxetine Systemic (s.c.) N/A Beh Not expressed Expressed SNRI

Duloxetine 32745472 TBI Systemic (s.c.) N/A Beh Not expressed Expressed SNRI hydrochloride

32745472 TBI Reboxetine mesylate Systemic (i.p.) N/A Beh Not expressed Not expressed NRI

5,7- dihydroxytryptamine + Intrathecal (i.t.) + Neurotoxin depleting serotonergic 32745472 TBI N/A Beh Not expressed Not expressed Desipramine Systemic (i.p.) fibers + TCA hydrochloride

Escitalopram 32745472 TBI Systemic (s.c.) N/A Beh Not expressed Expressed SSRI hydrochloride

Escitalopram + Systemic (i.p.) + 32745472 TBI N/A Beh Not expressed Expressed SSRI + α -adrenoceptor antagonist Atipamezole Systemic (s.c.) 2

5,7- dihydroxytryptamine + Systemic (i.t.) + Neurotoxin depleting serotonergic 32745472 TBI Desipramine Systemic (i.p.) + N/A Beh Not expressed Not expressed fibers + TCA + SSRI hydrochloride + Systemic (s.c.) Escitalopram

Subcutaneous 30286616 Naïve Sumatriptan succinate N/A Beh Expressed Not expressed 5-HT receptor agonist osmotic minipumps 1

Orally administered 32315711 PSNL Celecoxib N/A Beh Not expressed Not expressed COX-2 inhibitor (p.o.)

OA MIA (late Orally administered 32315711 Celecoxib N/A Beh Not expressed Not expressed COX-2 inhibitor stage) (p.o.)

Not expressed for 12818952 Naïve Isoflurane Gaseous (inhaled) Isoflurane Eph Expressed isoflurane above 1.2 General anaesthetic MAC

Abbreviations: SNL - spinal nerve ligation model; TBI - traumatic brain injury; OA MIA - monoiodoacetate model of osteoarthritis; PSNL - partial sciatic nerve ligation; BLS - bright light stress; PAG - periaqueductal grey; i.p. - intraperitoneal, i.th. - intrathecal (L4/L5 - lumbar 4/5), Beh - behaviour, Eph - in vivo electrophysiology; EMG - electromyography; IHC - immunohistochemistry; MAC - minimum alveolar anesthetic concentration; TCA - tricyclid antidepresant; SSRI - selective serotonin reuptake inhibitor; NRI - selective noradrenaline reuptake inhibitor; SNRI - selective serotonin- noradrenaline reuptake inhibitor; MOR - μ-opioid receptor; KOR - κ-opioid receptor; DOR - δ-opioid receptor; COX2 - cyclooxygenase 2.