Alcohol-induced sedation and synergistic interactions between alcohol and morphine: A key mechanistic role for Toll-like receptors and MyD88-dependent signaling

作者：Corrigan Frances; Wu Yue; Tuke Jonathan; Coller Janet K; Rice Kenner C; Diener Kerrilyn R; Hayball John D; Watkins Linda R; Somogyi Andrew A; Hutchinson Mark R^*

来源：Brain, Behavior, and Immunity, 2015, 45: 245-252.

DOI：10.1016/j.bbi.2014.12.019

• Drug interactions
• Toll like receptors
• Myeloid differentiation factor 88
• Cytokines
• Naloxone
• Drug overdose

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-kappa B, Interleukin-1 beta (IL-1 beta; as a downstream proinflammatory effector molecule) and the mu opioid receptor (MOR; as a classical site for morphine action) in acute alcohol-induced sedation (4.5 g/kg) and alcohol (2.5 g/kg) interaction with morphine (5 mg/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-kappa B, TLR4 and Interleukin-1 beta. 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-kappa B-, TLR2- and MyD88-dependent, but did not involve TLR4 or Interleukin-1 beta. Morphine-alcohol interactions caused acute elevations in microglial cell counts and NF-kappa B-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.

• 出版日期2015-3
• 单位NIH