Binge-Like Exposure to Ethanol Enhances Morphine's Anti-nociception in B6 Mice

Abstract

Elevation of the blood ethanol concentration (BEC) to > 80 mg/dL (17.4 mM) after binge drinking enhances inflammation in brain and neuroimmune signaling pathways. Morphine abuse is frequently linked to excessive drinking. Morphine exerts its actions mainly via the seven transmembrane G-protein-coupled mu opioid receptors (MORs). Opioid use disorders (OUDs) include combination of opioids with alcohol, leading to opioid overdose-related deaths. We hypothesized that binge drinking potentiates onset and progression of OUD. Using C57BL/6J (B6) mice, we first characterized time-dependent inflammatory gene expression change as molecular markers using qRT-PCR within 24 h after binge-like exposure to high-dose, high-concentration ethanol (EtOH). The mice were given one injection of EtOH (5 g/kg, 42% v/v, i.g.) and sacrificed at 2.5 h, 5 h, 7.5 h, or 24 h later. Inflammatory cytokines interleukin (IL)-1β, IL-6, and IL-18 were elevated in both the striatum (STr) and the nucleus accumbens (NAc) of the mice. We then investigated the expression profile of MOR in the STr at 2 min, 5 h, or 24 h after the first EtOH injection and at 24 h and 48 h after the third injection. This binge-like exposure to EtOH upregulated MOR expression in the STr and NAc, an effect that could enhance morphine's anti-nociception. Therefore, we examined the impact of binge-like exposure to EtOH on morphine's anti-nociception at the behavioral level. The mice were treated with or without 3-d binge-like exposure to EtOH, and the anti-nociceptive changes were evaluated using the hot-plate test 24 h after the final (3rd) EtOH injection with or without a cumulative subcutaneous dose (0, 0.1, 0.3, 1.0, and 3.0 mg/kg) of morphine at intervals of 30 min. The response curve of the mice given EtOH was shifted to the left, showing enhanced latency to response to morphine up to 3 mg/kg. Furthermore, co-treatment with the MOR antagonist naltrexone blocked morphine's anti-nociception in animals given either EtOH or saline. This confirms that MOR is involved in binge-like exposure to EtOH-induced changes in morphine's anti-nociception. Our results suggest that EtOH enhanced latency to analgesic response to morphine, and such effect might initiate the onset and progression of OUDs.

Altered patterns of fractional amplitude of low-frequency fluctuation and regional homogeneity in abstinent methamphetamine-dependent users

“…A study compared heroin users with and without relapse found that relapsed heroin users had increased ReHo in the right caudate 45 . Among individuals with internet gaming disorder, ALFF values of the bilateral putamen were higher before cognitive based treatment (CBT), while ALFF of left putamen was lower after CBT compared to HCs 46 . Chronic active smokers showed significantly increased fALFF in the right caudate, relative to HCs 47 , 48 .…”

Effects of alcohol on skeletal muscle contractile performance in male and female mice

“…Blood was then collected from the inferior vena cava into EDTA coated syringes and the animal was euthanized via cardioectomy while still deeply anesthized. Blood was only collected from animals at the 1 hour time point as unpublished data in our laboratory as well as multiple published reports have shown this dose of alcohol (or higher doses) is completely cleared from the blood by 8-12h post intoxication [ 12 – 14 ]. Blood was centrifuged for 10min at 10,000g for isolation of plasma which was stored at -80˚C until analysis of blood alcohol concentration.…”

Transcranial Direct Current Stimulation (tDCS) Induces Analgesia in Rats with Neuropathic Pain and Alcohol Abstinence

“…Neuropathic pain (NP) is a relevant clinical problem since it is severely debilitating and largely resistant to treatment because its mechanisms are poorly understood [1]. Similarly, alcohol abuse is an extremely serious public health problem because alcohol is the most widely used addictive substance worldwide [2]. Alcohol consumption is also a risk factor for many chronic diseases, with its effects dependent on volume, alcohol content, and frequency of use [2,3].…”

“…Similarly, alcohol abuse is an extremely serious public health problem because alcohol is the most widely used addictive substance worldwide [2]. Alcohol consumption is also a risk factor for many chronic diseases, with its effects dependent on volume, alcohol content, and frequency of use [2,3]. Taken together, these conditions change neurotransmitter levels, leading to changes in widespread modulation of neuronal activity [4].…”

“…It should also be stressed that both chronic pain and alcohol exposure/withdrawal lead to modifications in both central and peripheral neuroinflammatory patterns [2,15,24]. For example, previous studies have reported altered patterns of cytokines and neurotrophic factors following inflammatory and chronic pain injury models throughout the cortex-brainstem-spinal cord axis [25,26].…”