International review of neurobiology最新文献

The treatment of neuropathic pain (NeP) often leads to partial or incomplete pain relief, with up to 40 % of patients being pharmaco-resistant. In this chapter the efficacy of neuromodulation techniques in treating NeP is reviewed. It presents a detailed evaluation of the mechanisms of action and evidence supporting the clinical use of the most common approaches like transcutaneous electrical nerve stimulation (TENS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), invasive motor cortex stimulation (iMCS), spinal cord stimulation (SCS), dorsal root ganglion stimulation (DRG-S), and peripheral nerve stimulation (PNS). Current literature suggests that motor cortex rTMS is effective for peripheral and central NeP, and TENS for peripheral NeP. Evidence for tDCS is inconclusive. DBS is reserved for research settings due to heterogeneous results, while iMSC has shown efficacy in a small randomized trial in neuropathic pain due to stroke and brachial plexus avulsion. SCS has moderate evidence for painful diabetic neuropathy and failed back surgery syndrome, but trials were not controlled with sham. DRG-S and PNS have shown positive results for complex regional pain syndrome and post-surgical neuropathic pain, respectively. Adverse effects vary, with non-invasive techniques showing local discomfort, dizziness and headache, and DBS and SCS hardware-related issues. To date, non-invasive techniques have been more extensively studied and some are included in international guidelines, while the evidence level for invasive techniques are less robust, potentially suggesting their use in a case-by-case indication considering patient´s preferences, costs and expected benefits.

Management of neuropathic pain is exceptionally challenging and development of new drugs and ways to optimize treatment effects in clinical practice are needed. Over the last decade, some of the mechanisms underlying placebo effects have been elucidated and some of the insights have the potential to improve the treatment for neuropathic pain. Research suggests that the increasing placebo responses observed in randomized controlled trials (RCTs) for neuropathic pain pose challenges for the development and availability of new effective pain medications. In neuropathic pain, these placebo responses are typically not controlled for the natural history of pain and other confounding factors. Thus, our knowledge about the magnitude and mechanisms of placebo effects in neuropathic pain is sparse. A few mechanistic studies investigating placebo effects by controlling for natural history of pain have found large placebo analgesia effects in neuropathic pain. Psychological factors such as expectations and emotions play a substantial role in inducing the placebo effects. Here, we review placebo effects and the psychological and neurobiological mechanisms contributing to the placebo effects. The knowledge obtained from studies of placebo mechanisms can help improve the information that can be obtained from RCTs and potentially improve development of new pain medications and optimize treatment of neuropathic pain in clinical practice.

Small fiber neuropathy (SFN) is a condition involving the small nerve fibers of the peripheral nervous system, specifically the thinly myelinated Aδ and unmyelinated C fibers. It is an increasingly acknowledged condition within the spectrum of neuropathic pain disorders, leading to a rise in diagnosed patients. SFN is characterized by neuropathic pain, that is often described as burning, and typically presents in the hands and feet ascending proximally. Since small nerve fibers are involved in the autonomic nervous system, SFN can also lead to autonomic dysfunction. In the clinical setting, SFN diagnosis is frequently based on the Besta Criteria, which include skin biopsy and quantitative sensory testing. For clinical trials, the ACTTION criteria are also recommended. However, the diagnostic process is often complex, prompting research towards more accessible diagnostic methods. The pathophysiology of SFN remains unclear, thereby challenging therapeutic strategies. A large variety of underlying conditions has been associated with SFN, including metabolic, immune-mediated, infectious, toxic and hereditary conditions. The discovery of genetic sodium channelopathies in SFN provides insight into its underlying mechanisms. Newly discovered mutations within these genes reveal that SFN often shows overlapping clinical presentations with other sodium channelopathies. This chapter provides an in-depth look at SFN, including its clinical features, diagnostic methods, underlying conditions and possible therapeutic strategies.

This chapter aims to review the current pharmacological options for neuropathic pain treatment, their mechanisms of action, and future directions for clinical practice. Achieving pain relief in neuropathic pain conditions remains a challenge in clinical practice. The field of pharmacotherapy for neuropathic pain has encountered significant difficulties in translating substantial advances in our understanding of the underlying pathophysiological mechanisms into clinically effective therapies. This chapter presents the drugs recommended for the pharmacotherapy of neuropathic pain, based on the widely accepted treatment guidelines formulated by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain. In addition to discussing how the evidence base is created as part of international consortia, the drugs are also examined in terms of their putative molecular mechanisms as well as pharmacological pleiotropy, i.e., their potential unspecific and multi-target effects resulting in modulation of neuronal hyperexcitability. The chapter closes with a discussion of potential future developments in the field.

In mammals, ethanol is metabolized to acetaldehyde mainly by the liver alcohol dehydrogenase (ADH), and acetaldehyde is subsequently oxidized to acetate by mitochondrial aldehyde dehydrogenase (ALDH2). The presence of an inactive variant of ALDH2 or the use of inhibitors of this enzyme leads to an accumulation of acetaldehyde after ethanol consumption, generating an aversive reaction that inhibits subsequent alcohol intake. However, experimental evidence shows that acetaldehyde has potent rewarding effects at the central level, suggesting that acetaldehyde would be responsible for the addictive effect of alcohol. Alda-1 is an organic molecule that acts as a pharmacological activator of ALDH2. Studies in animal models of alcohol use disorders (AUD; i.e. alcoholism) have shown that Alda-1 can inhibit the acquisition, the chronic intake, and the relapse of alcohol consumption. These effects are reversible without any effects on water consumption or other natural reinforcer such as saccharin. It has also been reported that Alda-1 can act as a protective agent from the toxic effects on various tissues and organs mediated by ethanol-derived acetaldehyde, including liver damage, cancer, and central nervous system (CNS) alterations. Using in silico tools such as molecular docking the identification of important molecular interactions between Alda-1 and ALDH2 has been demonstrated, identifying new molecules with higher pharmacological features. Thus, there is now preclinical evidence supporting the use of activators of ALDH2 as a pharmacological strategy for the treatment of AUD.

For decades, psychedelics have been investigated for the treatment of psychiatric disorders. Specifically, evidence suggests that psychedelics may have therapeutic potential for the treatment of alcohol use disorder. Several studies with classic psychedelics, including LSD and psilocybin, show promising results, with psychedelics decreasing alcohol drinking and promoting abstinence in individuals with alcohol use disorder. In the last two decades, ayahuasca has emerged as another psychedelic with therapeutic potential for alcohol use disorder. Although its use by indigenous people from South America has been reported for thousands of years, ayahuasca, an Amazonian brewed beverage used in rituals, has gained attention in recent decades due to its reported effects in the central nervous system. Ayahuasca is a hallucinogenic beverage produced from the decoction of Banisteriopsis caapi and Psychotria viridis, plants that contain β-carbolines and N,N-dimethyltryptamine (DMT), respectively. The majority of clinical studies investigating ayahuasca for the treatment of alcohol use disorder are retrospective, and all show a significant decrease in alcohol use among ayahuasca users. Corroborating the clinical evidence, pre-clinical studies also have demonstrated that ayahuasca can block several of the abuse-related effects of alcohol. This chapter reviews the accumulating evidence from clinical and pre-clinical studies suggesting that ayahuasca may be a promising new pharmacotherapy for the treatment of alcohol use disorders, and discusses the potential mechanisms involved in these and other effects of ayahuasca.

Cannabidiol (CBD) modulates aversive memory and its extinction, with potential implications for treating anxiety- and stress-related disorders. Here, we summarize and discuss scientific evidence showing that CBD administered after the acquisition (consolidation) and retrieval (reconsolidation) of fear memory attenuates it persistently in rats and mice. CBD also reduces fear expression and enhances fear extinction. These effects involve the activation of cannabinoid type-1 (CB1) receptors in the dorsal hippocampus, bed nucleus of stria terminalis, and medial prefrontal cortex, comprising the anterior cingulate, prelimbic, and infralimbic subregions. Serotonin type-1A (5-HT1A) receptors also mediate some CBD effects on fear memory. CBD effects on fear memory acquisition vary, depending on the aversiveness of the conditioning procedure. While rodent findings are relatively consistent and encouraging, human studies investigating CBD's efficacy in modulating aversive/traumatic memories are still limited. More studies are needed to investigate CBD's effects on maladaptive, traumatic memories, particularly in post-traumatic stress disorder patients.

In this chapter we explored the growing interest in cannabinoids, particularly cannabidiol (CBD), over the last two decades due to their potential therapeutic applications in neurodegenerative and psychiatric disorders. CBD, a major non-psychotomimetic compound derived from Cannabis sativa, is highlighted as a safer alternative to other cannabinoids like Δ9-tetrahydrocannabinol (THC). Clinical trials have been investigating CBD formulations for conditions such as schizophrenia, multiple sclerosis, Alzheimer's, Parkinson's diseases, and stress-related disorders. However, limited access to CBD-approved formulations primarily due to their high-cost and concerns about the quality of market-available products, challenges regulatory agencies globally. The pharmacokinetics of CBD, especially after oral administration, present challenges with erratic absorption and low bioavailability. CBD's "promiscuous" pharmacodynamics involve interactions with various targets beyond the endocannabinoid system, complicating precise dosing in therapeutic interventions. This chapter delves into CBD's dose-response curves, revealing complexities that pose challenges in clinical practice. Nanobiotechnology emerges as a promising solution, with recent developments showing improved bioavailability, stability, and reduced toxicity through nanoencapsulation of CBD. While this phytocannabinoid holds immense promise in neuropsychopharmacology, we provided a comprehensive overview of the current state of CBD research and suggests potential future directions regarding the pharmacology of CBD, harnessing the benefits of this intriguing compound.

Anxiety disorders are highly prevalent psychiatric disorders, characterized by a chronic course and often accompanied by comorbid symptoms that impair functionality and decrease quality of life. Despite advances in basic and clinical research in our understanding of these disorders, currently available pharmacological options are associated with limited clinical benefits and side effects that frequently lead to treatment discontinuation. Importantly, a significant number of patients do not achieve remission and live with lifelong residual symptoms that limit daily functioning. Since the 1970s, basic and clinical research on cannabidiol (CBD), a non-psychotomimetic compound found in the Cannabis sativa plant, has indicated relevant anxiolytic effects, garnering attention for its therapeutic potential as an option in anxiety disorder treatment. This chapter aims to review the history of these studies on the anxiolytic effects of CBD within the current understanding of anxiety disorders. It highlights the most compelling current evidence supporting its anxiolytic effects and explores future perspectives for its clinical use in anxiety disorders.

Timely and accurate diagnosis of neuropathic pain is critical for optimizing therapeutic outcomes and minimizing treatment delays. According to current standards, the diagnosis of definite neuropathic pain requires objective confirmation of a lesion or disease affecting the somatosensory nervous system. This can be provided by specialized neurophysiological techniques as conventional methods like nerve conduction studies and somatosensory evoked potentials may not be sufficient as they do not assess pain pathways. These specialized techniques apply various stimuli, such as thermal, electrical, or mechanical, alongside assessments of spinal/cortical potential or electromyographic reflex recordings. The selection of techniques is guided by the patient's clinical history and examination. The most common neurophysiological tests used in clinical practice are pain-related evoked potentials (PREPs) providing an objective evaluation of nociceptive pathways. Four types of PREPs are employed: laser evoked potentials, contact-heat evoked potentials, intra-epidermal electrical stimulation evoked potentials, and pinprick evoked potentials, with the two former ones being the most robust and reliable ones. These techniques investigate small-diameter fibers, primarily Aδ-fibers, and spinothalamic tracts allowing the identification of peripheral or central nervous system lesions. Yet, they are limited in capturing neuronal mechanisms underlying neuropathic pain or in providing objective quantification of pain sensation. Two neurophysiological measures which investigate the pain system beyond its integrity are the nociceptive withdrawal reflex and the N13 component of somatosensory evoked potentials. Both of these methods are more commonly used in research than clinical practice, but they pose interesting approaches to quantify central sensitization, a key underlying mechanism of neuropathic pain. Future investigations in neuropathic pain are therefore warranted.