title: Alcohol-induced sedation and synergistic interactions between alcohol and morphine: a key mechanistic role for Toll-like receptors and MyD88-dependent signaling.
abstract: Increasing evidence demonstrates induction of proinflammatory Toll-like receptor (TLR) 2 and TLR4 signaling by morphine and, TLR4 signaling by alcohol; thus indicating a common site of drug action and a potential novel innate immune-dependent hypothesis for opioid and alcohol drug interactions. Hence, the current study aimed to assess the role of TLR2, TLR4, MyD88 (as a critical TLR-signaling participant), NF-κB, Interleukin-1β (IL-1β; as a downstream proinflammatory effector molecule) and the μ opioid receptor (MOR; as a classical site for morphine action) in acute alcohol-induced sedation (4.5g/kg) and alcohol (2.5g/kg) interaction with morphine (5mg/kg) by assessing the loss of righting reflex (LORR) as a measure of sedation. Wild-type male Balb/c mice and matched genetically-deficient TLR2, TLR4, and MyD88 strains were utilized, together with pharmacological manipulation of MOR, NF-κB, TLR4 and Interleukin-1β. Alcohol induced significant LORR in wild-type mice; this was halved by MyD88 and TLR4 deficiency, and surprisingly nearly completely eliminated by TLR2 deficiency. In contrast, the interaction between morphine and alcohol was found to be MOR-, NF-κB-, TLR2- and MyD88-dependent, but did not involve TLR4 or Interleukin-1β. Morphine-alcohol interactions caused acute elevations in microglial cell counts and NF-κB-p65 positive cells in the motor cortex in concordance with wild-type and TLR2 deficient mouse behavioral data, implicating neuroimmunopharmacological signaling as a pivotal mechanism in this clinically problematic drug-drug interaction.
authors.affiliation: Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Frances
authors.initials: F
authors.lastname: Corrigan
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: School of Mathematical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tuke
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Janet K
authors.initials: JK
authors.lastname: Coller
authors.affiliation: Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism National Institutes of Health, Rockville, MD, USA.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia; Experimental Therapeutics Laboratory, Hanson Institute & Sansom Institute, Adelaide, South Australia, Australia; School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Kerrilyn R
authors.initials: KR
authors.lastname: Diener
authors.affiliation: Experimental Therapeutics Laboratory, Hanson Institute & Sansom Institute, Adelaide, South Australia, Australia; School of Pharmacy & Medical Sciences, University of South Australia, Adelaide, South Australia, Australia; School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Hayball
authors.affiliation: Department of Psychology and Neuroscience and The Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA.
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia; Centre for Translational Cancer Research, University of Adelaide, Adelaide, South Australia, Australia; Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
authors.affiliation: Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia. Electronic address: mark.hutchinson@adelaide.edu.au.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D053594:Myeloid Differentiation Factor 88 / Q000187:drug effects* / Q000235:genetics; D016328:NF-kappa B / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012021:Reflex, Abnormal; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000187:drug effects* / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000187:drug effects* / Q000235:genetics
chemical_list: D000701:Analgesics, Opioid; D002492:Central Nervous System Depressants; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D017450:Receptors, Opioid, mu; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000431:Ethanol; D009020:Morphine
keywords: Cytokines; Drug interactions; Drug overdose; Myeloid differentiation factor 88; Naloxone; Toll like receptors