Alcohol use and the pain system

The World Health Organization’s epidemiological data from 2016 revealed that while 57% of the global population aged 15 years or older had abstained from drinking alcohol in the previous year, more than half of the population in the Americas, Europe, and Western Pacific consumed alcohol. The spectrum of alcohol use behavior is broad: low-risk use (sensible and in moderation), at-risk use (e.g., binge drinking), harmful use (misuse) and dependence (alcoholism; addiction; alcohol use disorder). The at-risk use and misuse of alcohol is associated with the transition to dependence, as well as many damaging health outcomes and preventable causes of premature death. Recent conceptualizations of alcohol dependence posit that the subjective experience of pain may be a significant contributing factor in the transition across the spectrum of alcohol use behavior. This narrative review summarizes the effects of alcohol at all levels of the pain system. The pain system includes nociceptors as sensory indicators of potentially dangerous stimuli and tissue damage (nociception), spinal circuits mediating defensive reflexes, and most importantly, the supraspinal circuits mediating nocifensive behaviors and the perception of pain. Although the functional importance of pain is to protect from injury and further or future damage, chronic pain may emerge despite the recovery from, and absence of, biological damage (i.e., in the absence of nociception). Like other biological perceptual systems, pain is a construction contingent on sensory information and a history of individual experiences (i.e., learning and memory). Neuroadaptations and brain plasticity underlying learning and memory and other basic physiological functions can also result in pathological conditions such as chronic pain and addiction. Moreover, the negative affective/emotional aspect of pain perception provides embodied and motivational components that may play a substantial role in the transition from alcohol use to dependence

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

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

Intraneuronal β-amyloid Accumulation: Aging HIV-1 Human and HIV-1 Transgenic Rat Brain

The prevalence of HIV-1 associated neurocognitive disorders (HAND) is significantly greater in older, relative to younger, HIV-1 seropositive individuals; the neural pathogenesis of HAND in older HIV-1 seropositive individuals, however, remains elusive. To address this knowledge gap, abnormal protein aggregates (i.e., β-amyloid) were investigated in the brains of aging (\u3e12 months of age) HIV-1 transgenic (Tg) rats. In aging HIV-1 Tg rats, double immunohistochemistry staining revealed abnormal intraneuronal β-amyloid accumulation in the prefrontal cortex (PFC) and hippocampus, relative to F344/N control rats. Notably, in HIV-1 Tg animals, increased β-amyloid accumulation occurred in the absence of any genotypic changes in amyloid precursor protein (APP). Furthermore, no clear amyloid plaque deposition was observed in HIV-1 Tg animals. Critically, β-amyloid was co-localized with neurons in the cortex and hippocampus, supporting a potential mechanism underlying synaptic dysfunction in the HIV-1 Tg rat. Consistent with these neuropathological findings, HIV-1 Tg rats exhibited prominent alterations in the progression of temporal processing relative to control animals; temporal processing relies, at least in part, on the integrity of the PFC and hippocampus. In addition, in post-mortem HIV-1 seropositive individuals with HAND, intraneuronal β-amyloid accumulation was observed in the dorsolateral PFC and hippocampal dentate gyrus. Consistent with observations in the HIV-1 Tg rat, no amyloid plaques were found in these post-mortem HIV-1 seropositive individuals with HAND. Collectively, intraneuronal β-amyloid aggregation observed in the PFC and hippocampus of HIV-1 Tg rats supports a potential factor underlying HIV-1 associated synaptodendritic damage. Further, the HIV-1 Tg rat provides a biological system to model HAND in older HIV-1 seropositive individuals

Intraneuronal β-Amyloid Accumulation: Aging HIV-1 Human and HIV-1 Transgenic Rat Brain

The prevalence of HIV-1 associated neurocognitive disorders (HAND) is significantly greater in older, relative to younger, HIV-1 seropositive individuals; the neural pathogenesis of HAND in older HIV-1 seropositive individuals, however, remains elusive. To address this knowledge gap, abnormal protein aggregates (i.e., β-amyloid) were investigated in the brains of aging (\u3e12 months of age) HIV-1 transgenic (Tg) rats. In aging HIV-1 Tg rats, double immunohistochemistry staining revealed abnormal intraneuronal β-amyloid accumulation in the prefrontal cortex (PFC) and hippocampus, relative to F344/N control rats. Notably, in HIV-1 Tg animals, increased β-amyloid accumulation occurred in the absence of any genotypic changes in amyloid precursor protein (APP). Furthermore, no clear amyloid plaque deposition was observed in HIV-1 Tg animals. Critically, β-amyloid was co-localized with neurons in the cortex and hippocampus, supporting a potential mechanism underlying synaptic dysfunction in the HIV-1 Tg rat. Consistent with these neuropathological findings, HIV-1 Tg rats exhibited prominent alterations in the progression of temporal processing relative to control animals; temporal processing relies, at least in part, on the integrity of the PFC and hippocampus. In addition, in post-mortem HIV-1 seropositive individuals with HAND, intraneuronal β-amyloid accumulation was observed in the dorsolateral PFC and hippocampal dentate gyrus. Consistent with observations in the HIV-1 Tg rat, no amyloid plaques were found in these post-mortem HIV-1 seropositive individuals with HAND. Collectively, intraneuronal β-amyloid aggregation observed in the PFC and hippocampus of HIV-1 Tg rats supports a potential factor underlying HIV-1 associated synaptodendritic damage. Further, the HIV-1 Tg rat provides a biological system to model HAND in older HIV-1 seropositive individuals

Sleep Deprivation and Neurological Disorders

Sleep plays an important role in maintaining neuronal circuitry, signalling and helps maintain overall health and wellbeing. Sleep deprivation (SD) disturbs the circadian physiology and exerts a negative impact on brain and behavioural functions. SD impairs the cellular clearance of misfolded neurotoxin proteins like α-synuclein, amyloid-β, and tau which are involved in major neurodegenerative diseases like Alzheimer\u27s disease and Parkinson\u27s disease. In addition, SD is also shown to affect the glymphatic system, a glial-dependent metabolic waste clearance pathway, causing accumulation of misfolded faulty proteins in synaptic compartments resulting in cognitive decline. Also, SD affects the immunological and redox system resulting in neuroinflammation and oxidative stress. Hence, it is important to understand the molecular and biochemical alterations that are the causative factors leading to these pathophysiological effects on the neuronal system. This review is an attempt in this direction. It provides up-to-date information on the alterations in the key processes, pathways, and proteins that are negatively affected by SD and become reasons for neurological disorders over a prolonged period of time, if left unattended

Sleep deprivation and neurological disorders

Sleep plays an important role in maintaining neuronal circuitry, signalling and helps maintain overall health and wellbeing. Sleep deprivation (SD) disturbs the circadian physiology and exerts a negative impact on brain and behavioural functions. SD impairs the cellular clearance of misfolded neurotoxin proteins like α-synuclein, amyloid-β, and tau which are involved in major neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. In addition, SD is also shown to affect the glymphatic system, a glial-dependent metabolic waste clearance pathway, causing accumulation of misfolded faulty proteins in synaptic compartments resulting in cognitive decline. Also, SD affects the immunological and redox system resulting in neuroinflammation and oxidative stress. Hence, it is important to understand the molecular and biochemical alterations that are the causative factors leading to these pathophysiological effects on the neuronal system. This review is an attempt in this direction. It provides up-to-date information on the alterations in the key processes, pathways, and proteins that are negatively affected by SD and become reasons for neurological disorders over a prolonged period of time, if left unattended

NLRP12 Inflammasome Expression in the Rat Brain in Response to LPS during Morphine Tolerance

Morphine, an effective but addictive analgesic, can profoundly affect the inflammatory response to pathogens, and long-term use can result in morphine tolerance. Inflammasomes are protein complexes involved in the inflammatory response. The nucleotide-binding oligomerization domain-like receptor (NLR) Family Pyrin Domain Containing (NLRP) 12 (NLRP12) inflammasome has been reported to have anti-inflammatory activity. In this study, we examined the expression of NLRP12 inflammasome related genes in the adult F344 rat brain in response to the bacterial endotoxin lipopolysaccharide (LPS) in the presence and absence of morphine tolerance. Morphine tolerance was elicited using the 2 + 4 morphine-pelleting protocol. On Day 1, the rats were pelleted subcutaneously with 2 pellets of morphine (75 mg/pellet) or a placebo; on Days 2 and 4 pellets were given. On Day 5, the animals were randomly assigned to receive either 250 µg/kg LPS or saline (i.p.). The expression of 84 inflammasome related genes in the rat brain was examined using a Ploymerase Chain Reaction (PCR) array. In response to LPS, there was a significant increase in the expression of the pro-inflammatory cytokine/chemokine genes interleukin-1 beta (Il-1β), interleukin-6 (Il-6), C-C motif chemokine ligand 2 (Ccl2), C-C motif chemokine ligand 7 (Ccl7), C-X-C motif chemokine ligand 1 (Cxcl1), and C-X-C motif chemokine ligand 3 (Cxcl3) and a significant decrease in the anti-inflammatory NLRP12 gene in both morphine-tolerant and placebo-control rats compared to saline-treated rats, although the changes were greater in the placebo-control animals. The Library of Integrated Network-Based Cellular Signatures’ (LINCS) connectivity map was used to analyze the list of affected genes to identify potential targets associated with the interactions of LPS and morphine tolerance. Our data indicate that, in the morphine tolerant state, the expression of NLRP12 and its related genes is altered in response to LPS and that the Vacuolar protein-sorting-associated protein 28 (VPS28), which is involved in the transport and sorting of proteins into sub-cellular vesicles, may be the key regulator of these alterations