A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia.

Background: Low dose naltrexone (LDN) is used off-label by many individuals with fibromyalgia to help manage their pain. There is no current systematic literature review summarising the evidence to support this use of LDN. The objectives of this study were to evaluate if patients with fibromyalgia prescribed LDN have reduced pain scores and greater quality of life compared with those allocated to placebo in randomized controlled trials. Secondly to determine if changes in inflammatory markers and brain structure and function are observed among patients with fibromyalgia taking LDN. Methods: Systematic literature searches were conducted in MEDLINE, Embase Classic + Embase, APA PsychInfo, and The Cochrane Library from inception to May 2022. Reference lists from the selected papers were cross-checked with database search results. Results: Three studies met our inclusion criteria for the assessment of efficacy, and two studies on potential LDN mechanisms. Results indicated some evidence to suggest LDN reduces pain and increases quality of life. One study reported baseline erythrocyte sedimentation rate (ESR) predicted LDN response (≥30% reduction in fibromyalgia symptoms) and a second study showed plasma concentrations of inflammatory biomarkers were lower after LDN treatment. To our knowledge, there are no brain imaging studies reporting the effect of LDN in patients with fibromyalgia. All studies were based on small sample sizes, were restricted to women and the risk of bias was assessed to be high. There is also some evidence of publication bias. Conclusion: The strength of evidence from randomized controlled trials to support the use of LDN among patients with fibromyalgia is low. Two small studies suggest ESR and cytokines may be involved in the mechanism by which LDN exerts its effects. Two trials (INNOVA and FINAL) are currently in progress, but further work is needed among men and different ethnic groups.

Torpor Does Not Influence Spatial Memory in Hibernating Golden-Mantled Ground Squirrels (Spermophilus [Callospermophilus] lateralis).

AbstractMammalian hibernation in ground squirrels is characterized by periods of torpor wherein body temperature approaches ambient temperature and metabolism is reduced to as low as 1/100th of active rates. It is unclear how hibernation affects long-term spatial memory, as tremendous remodeling of neurons is associated with torpor use. Given the suspected links between remodeling and memory formation and retention, we examined long-term spatial memory retention throughout a hibernation season. Animals were trained on a Barnes maze before entering torpor. Animals were tested for memory retention once a month throughout a hibernation season. Results indicate marked variation between individuals. Some squirrels retained memory across multiple torpor bouts, while other squirrels did not. No relationship was found between the number of torpor bouts, duration of bouts, or time spent torpid on long-term memory retention. However, that some squirrels successfully retain memory suggests that the profound remodeling of dendritic spines during torpor does not always lead to memory loss.

Low-dose naltrexone as a treatment for chronic fatigue syndrome.

Naltrexone is used as an off-label treatment in low doses for several chronic immune-modulated disorders in many countries. Although only small-scale clinical trials have been performed, these suggest efficacy in several diseases including Crohn's disease, fibromyalgia and Gulf War Illness. Despite numerous internet reports of response to low-dose naltrexone (LDN), no clinical trials exist in people with chronic fatigue syndrome. This condition is characterised by chronic profound fatigue, postexertional malaise, pain and autonomic and neurocognitive disturbances. This series of three case reports compiled by people with long-term ill-health due to chronic fatigue syndrome shows the range of responses they observed when taking LDN, from life changing to a reduction in some symptoms only. Treatment doses ranged from 4 to 12 mg. Clinical trials may be warranted to explore the potential use of naltrexone in people with these debilitating illnesses which currently have no licensed treatments available.

Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis.

BACKGROUND: Naltrexone is an opioid antagonist used in many different conditions, both licensed and unlicensed. It is used at widely varying doses from 3 to 250 mg. The aim of this review was to extensively evaluate the safety of oral naltrexone by examining the risk of serious adverse events and adverse events in randomised controlled trials of naltrexone compared to placebo. METHODS: A systematic search of the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, other databases and clinical trials registries was undertaken up to May 2018. Parallel placebo-controlled randomised controlled trials longer than 4 weeks published after 1 January 2001 of oral naltrexone at any dose were selected. Any condition or age group was included, excluding only studies in opioid or ex-opioid users owing to possible opioid/opioid antagonist interactions. The systematic review used the guidance of the Cochrane Handbook and Preferred Reporting Items for Systematic Reviews and Meta-analyses harms checklist throughout. Numerical data were independently extracted by two people and cross-checked. Risk of bias was assessed with the Cochrane risk-of-bias tool. Meta-analyses were performed in R using random effects models throughout. RESULTS: Eighty-nine randomised controlled trials with 11,194 participants were found, studying alcohol use disorders (n = 38), various psychiatric disorders (n = 13), impulse control disorders (n = 9), other addictions including smoking (n = 18), obesity or eating disorders (n = 6), Crohn's disease (n = 2), fibromyalgia (n = 1) and cancers (n = 2). Twenty-six studies (4,960 participants) recorded serious adverse events occurring by arm of study. There was no evidence of increased risk of serious adverse events for naltrexone compared to placebo (risk ratio 0.84, 95% confidence interval 0.66-1.06). Sensitivity analyses pooling risk differences supported this conclusion (risk difference -0.01, 95% confidence interval -0.02-0.00) and subgroup analyses showed that results were consistent across different doses and disease groups. Secondary analysis revealed only six marginally significant adverse events for naltrexone compared to placebo, which were of mild severity. CONCLUSIONS: Naltrexone does not appear to increase the risk of serious adverse events over placebo. These findings confirm the safety of oral naltrexone when used in licensed indications and encourage investments to undertake efficacy studies in unlicensed indications. TRIAL REGISTRATION: PROSPERO 2017 CRD42017054421 .

Intermittent streptozotocin administration induces behavioral and pathological features relevant to Alzheimer's disease and vascular dementia.

RATIONALE: Diabetes mellitus (DM) is a major risk factor for Alzheimer's disease and vascular dementia. Few animal models exist that focus on the metabolic contributions to dementia onset and progression. Thus, there is strong scientific rationale to explore the effects of streptozotocin (STZ), a diabetogenic compound, on vascular and inflammatory changes within the brain. OBJECTIVE AND METHODS: The present study was designed to evaluate the effect of staggered, low-dose administration of STZ on behavioral and cognitive deficits, neuroinflammation, tau pathology, and histopathological alterations related to dementia. RESULTS: Staggered administration (Days 1, 2, 3, 14, 15) of streptozotocin (40 mg/kg/mL) induced a diabetic-like state in mice, resulting in sustained hyperglycemia. STZ-treated animals displayed memory deficits in the novel object recognition task as well as increased tau phosphorylation and increased neuroinflammation. Additionally, STZ led to altered insulin signaling, exhibited by decreased plasma insulin and decreased levels of insulin degrading enzyme and pAKT within the hippocampus. CONCLUSIONS: STZ-treated animals exhibit cognitive deficits and histopathological changes seen in dementia. This model of dementia warrants continued investigation to better understand the role that DM plays in dementia-related alterations.

Effect of acute lipopolysaccharide-induced inflammation in intracerebroventricular-streptozotocin injected rats.

Lipopolysaccharide (LPS) is often used to investigate the exacerbatory effects of an immune-related challenge in transgenic models of various neurodegenerative diseases. However, the effects of this inflammatory challenge in an insulin resistant brain state, as seen in diabetes mellitus, a major risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), is not as well characterized. We investigated the effects of an LPS-induced inflammatory challenge on behavioral and biological parameters following intracerebroventricular (ICV) injection of streptozotocin (STZ) in male Sprague-Dawley rats. Subjects received a one-time bilateral ICV infusion of STZ (25 mg/mL, 8 µL per ventricle) or ACSF. One week following ICV infusions, LPS (1 mg/mL, i.p.) or saline was administered to activate the immune system. Behavioral testing began on the 22nd day following STZ-ICV infusion, utilizing the open field and Morris water maze (MWM) tasks. Proteins related to immune function, learning and memory, synaptic plasticity, and key histopathological markers observed in VaD and AD were evaluated. The addition of an LPS-induced immune challenge partially attenuated spatial learning and memory deficits in the MWM in STZ-ICV injected animals. Additionally, LPS administration to STZ-treated animals partially mitigated alterations observed in several protein levels in STZ-ICV alone, including NR2A, GABA(B1), and ß-amyloid oligomers. These results suggest that an acute LPS-inflammatory response has a modest protective effect against some of the spatial learning and memory deficits and protein alterations associated with STZ-ICV induction of an insulin resistant brain state.

Postnatal alterations in GABAB receptor tone produce sensorimotor gating deficits and protein level differences in adulthood.

The GABA transmitter system plays a vital role in modulating synaptic formation and activity during development. The GABAB receptor subtype in particular has been implicated in cell migration, promotion of neuronal differentiation, neurite outgrowth, and synapse formation but it's role in development is not well characterized. In order to investigate the effects of brief alterations in GABAB signaling in development, we administered to rats the GABAB agonist baclofen (2.0mg/kg) or antagonist phaclofen (0.3mg/kg) on postnatal days 7, 9, and 12, and evaluated sensorimotor gating in adulthood. We also examined tissue for changes in multiple proteins associated with GABAB receptor function and proteins associated with synapse formation. Our data indicate that early postnatal alterations to GABAB receptor-mediated signaling produced sex differences in sensorimotor gating in adulthood. Additionally, we found differences in GABAB receptor subunits and kalirin protein levels in the brain versus saline treated controls. Our data demonstrate that a subtle alteration in GABAB receptor function in early postnatal life induces changes that persist into adulthood.

Chronic ketamine produces altered distribution of parvalbumin-positive cells in the hippocampus of adult rats.

The underlying mechanisms of schizophrenia pathogenesis are not well understood. Increasing evidence supports the glutamatergic hypothesis that posits a hypofunction of the N-methyl D-aspartate (NMDA) receptor on specific gamma amino-butyric acid (GABA)-ergic neurons may be responsible for the disorder. Alterations in the GABAergic system have been observed in schizophrenia, most notably a change in the expression of parvalbumin (PV) in the cortex and hippocampus. Several reports also suggest abnormal neuronal migration may play a role in the etiology of schizophrenia. The current study examined the positioning and distribution of PV-positive cells in the hippocampus following chronic treatment with the NMDA receptor antagonist ketamine. A robust increase was found in the number of PV-positive interneurons located outside the stratum oriens (SO), the layer where most of these cells are normally localized, as well as an overall numerical increase in CA3 PV cells. These results suggest ketamine leads to an abnormal distribution of PV-positive cells, which may be indicative of aberrant migratory activity and possibly related to the Morris water maze deficits observed. These findings may also be relevant to alterations observed in schizophrenia populations.

Baclofen administration alters fear extinction and GABAergic protein levels.

The investigation of GABAergic systems in learning and extinction has principally focused on ionotropic GABA(A) receptors. Less well characterized is the metabotropic GABA(B) receptor, which when activated, induces a more sustained inhibitory effect and has been implicated in regulating oscillatory activity. Few studies have been carried out utilizing GABA(B) ligands in learning, and investigations of GABA(B) in extinction have primarily focused on interactions with drugs of abuse. The current study examined changes in GABA(B) receptor function using the GABA(B) agonist baclofen (2 mg/mL) or the GABA(B) antagonist phaclofen (0.3 mg/mL) on trace cued and contextual fear conditioning and extinction. The compounds were either administered during training and throughout extinction in Experiment 1, or starting 24 h after training and throughout extinction in Experiment 2. All drugs were administered 1 mL/kg via intraperitoneal injection. These studies demonstrated that the administration of baclofen during training and extinction trials impaired animals' ability to extinguish the fear association to the CS, whereas the animals that were administered baclofen starting 24 h after training (Experiment 2) did display some extinction. Further, contextual fear extinction was impaired by baclofen in both experiments. Tissue analyses suggest the cued fear extinction deficit may be related to changes in the GABA(B2) receptor subunit in the amygdala. The data in the present investigation demonstrate that GABA(B) receptors play an important role in trace cued and contextual fear extinction, and may function differently than GABA(A) receptors in learning, memory, and extinction.

Examination of ketamine-induced deficits in sensorimotor gating and spatial learning.

Subanesthetic administration of the NMDA receptor antagonist ketamine has been suggested to have utility in several therapeutic domains; however, its recreational use has exceeded its therapeutic applications. Ketamine has been utilized to investigate NMDA receptor-mediated learning and memory and to model disorders such as schizophrenia. The utility of ketamine in relation to schizophrenia is based on a proposed mechanism of the disorder being associated with reduced NMDA receptor function within a subset of GABAergic neurons. The examination of ketamine with relevance to the above topics has produced valuable data; however, there exists a great deal of variability in the literature regarding dosage and timing of administration to examine ketamine-induced deficits. In the below experiments we sought to identify the minimal subanesthetic dosage and schedule of ketamine administrations that would produce behavioral deficits in multiple tasks with relevance to the above investigations. We evaluated sensorimotor gating as well as spatial learning and memory in the Morris water task utilizing different doses of ketamine. Our data indicate that an 8 mg/kg subcutaneous dose of ketamine was the minimal dose to produce impairments in both sensorimotor gating and spatial learning.

Administration of donepezil does not rescue galanin-induced spatial learning deficits.

The neuropeptide galanin inhibits the evoked release of several neurotransmitters including acetylcholine and modulates adenylate cyclase (AC) activity. Galanin has also been established to impair various forms of learning and memory in rodents. However, whether galanin produces learning deficits by inhibiting cholinergic activity or decreasing AC function has not been clearly established. The current study investigated if donepezil, an acetylcholinesterase inhibitor utilized in Alzheimer's disease, could rescue galanin-induced Morris water task deficits in rats. The results demonstrated that donepezil did not alter the previously established deficits induced by galanin. These findings suggest that galanin-mediated spatial learning deficits may be unrelated to its modulation of the cholinergic system.

Deficits in emotional learning and memory in an animal model of schizophrenia.

Alterations in N-methyl-D-aspartate (NMDA) receptor function have been linked to numerous behavioral deficits and neurochemical alterations. Recent investigations have begun to explore the role of NMDA receptor function on principally inhibitory neurons and their role in network function. One of the prevailing models of schizophrenia proposes a reduction in NMDA receptor function on inhibitory interneurons and the resulting disinhibition may give rise to aspects of the disorder. Studies using NMDA receptor antagonists such as PCP and ketamine have induced schizophrenia-like behavioral deficits in animal model systems as well as changes in inhibitory circuits. The current study investigated whether the administration of a subanesthetic dose of ketamine (8 mg/kg subcutaneously), that disrupts sensorimotor gating, also produces impairments in a Pavlovian emotional learning and memory task. We utilized both standard delay and trace cued and contextual fear conditioning (CCF) paradigms to examine if ketamine produces differential effects when the task is more difficult and relies on connectivity between specific brain regions. Rats administered ketamine displayed no significant deficits in cued or contextual fear following the delay conditioning protocol. However, ketamine did produce a significant impairment in the more difficult trace conditioning protocol. Analyses of tissue from the hippocampus and amygdala indicated that the administration of ketamine produced an alteration in GABA receptor protein levels differentially depending on the task. These data indicate that 8 mg/kg of ketamine impairs learning in the more difficult emotional classical conditioning task and may be related to altered signaling in GABAergic systems.