International Review Of Neurobiology[JOURNAL]
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200 papers
Oro-pharyngeal mucosal microbiome alternations causing immune system dysregulation in schizophrenia.
Krishnan D, Ghosh P, Lakshman N … +2 more , Justin A, Ramasamy S
Int Rev Neurobiol · 2025 · PMID 40414631 · Publisher ↗
Schizophrenia is a chronic and thoughtful psychological disorder that affects a person's thinking, feelings, and behaviours. Multi-factorial genetic, environmental, and neurological variables cause it. Recently, more res...
Schizophrenia is a chronic and thoughtful psychological disorder that affects a person's thinking, feelings, and behaviours. Multi-factorial genetic, environmental, and neurological variables cause it. Recently, more research focused on the human microbiome, which alters the immune system and develops adverse health effects on the human body. The study discusses a possible relationship between the oropharyngeal microbiome and schizophrenia. According to recent studies, the oropharyngeal microbiome may alter the immune system in the human body and cause various psychiatric disorders, including schizophrenia. The oropharyngeal microbiome can cause schizophrenia either by affecting the genes, chromosomes, and immune system in the human body. Additionally, it examines the combined mechanism of how the oropharyngeal microbiome's alterations lead to genetic abnormalities and immune dysregulation in schizophrenia. By combining the various approaches, this chapter offers a comprehensive view of the oropharyngeal microbiome's role in schizophrenia and suggests that microbial alterations could serve as biomarkers or therapeutic targets for the disorder.
Dysbiosis significantly elevates the probability of altered affective function in Alzheimer disease (AD).
Kumar H, Dhanjal DS, Dhalaria R … +3 more , Kimta N, Cimler R, Kuča K
Int Rev Neurobiol · 2025 · PMID 40414630 · Publisher ↗
Changes in the makeup of gut microbiota are linked to many neuropsychiatric diseases. Although the exact connection between gut dysbiosis and brain dysfunction is not yet fully understood, but recent data suggests that g...
Changes in the makeup of gut microbiota are linked to many neuropsychiatric diseases. Although the exact connection between gut dysbiosis and brain dysfunction is not yet fully understood, but recent data suggests that gut dysbiosis may contribute to the development of Alzheimer's disease (AD) by promoting neuroinflammation, insulin resistance, oxidative stress, and amyloid-beta (Aβ) aggregation. Gut dysbiosis in animal models is primarily characterized by an elevated ratio of Firmicutes/Bacteroidetes which may lead to the accumulation of amyloid precursor protein (APP) in the intestine, in the early stages of AD. Probiotics play a significant role in preventing against the symptoms of AD by restoring gut-brain homeostasis. This chapter provides an overview of the gut microbiota and its dysregulation in etiology of AD. Moreover, novel insights into alteration of the composition of gut microbiota as a preventive or therapeutic approach to AD are discussed.
Regional and interregional functional and structural brain abnormalities in neuropathic pain.
El-Sayed R, Davis KD
Int Rev Neurobiol · 2024 · PMID 39580223 · Publisher ↗
Neuropathic pain is a severe form of chronic pain due to a lesion or disease of the somatosensory nervous system. Here we provide an overview of the neuroimaging approaches that can be used to assess brain abnormalities...
Neuropathic pain is a severe form of chronic pain due to a lesion or disease of the somatosensory nervous system. Here we provide an overview of the neuroimaging approaches that can be used to assess brain abnormalities in a chronic pain condition, with particular focus on people with neuropathic pain and then summarize the findings of studies that applied these methodologies to study neuropathic pain. First, we review the most commonly used approaches to examine grey and white matter abnormalities using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) and then review functional neuroimaging techniques to measure regional activity and inter-regional communication using functional MRI, electroencephalography (EEG) and magnetoencephalography (MEG). In neuropathic pain the most prominent structural abnormalities have been found to be in the primary somatosensory cortex, insula, anterior cingulate cortex and thalamus, with differences in volume directionality linked to neuropathic pain symptomology. Functional connectivity findings related to treatment outcome point to a potential clinical utility. Some prominent abnormalities in neuropathic pain identified with EEG and MEG throughout the dynamic pain connectome are slowing of alpha activity and higher regional oscillatory activity in the theta and alpha band, lower low beta and higher high beta band power. Finally, connectivity and coupling findings placed into context how regional abnormalities impact the networks and pathways of the dynamic pain connectome. Overall, functional and structural neuroimaging have the potential to identify predictive biomarkers that can be used to guide development of personalized pain management of neuropathic pain.
Quantitative Sensory Testing - From bench to bedside.
Hughes S, Vollert J, Freeman R … +1 more , Forstenpointner J
Int Rev Neurobiol · 2024 · PMID 39580222 · Publisher ↗
The methodology of Quantitative Sensory Testing (QST) comprises standardized testing procedures, which provide information of the integrity of the somatosensory nervous system. Over the years, different protocols have be...
The methodology of Quantitative Sensory Testing (QST) comprises standardized testing procedures, which provide information of the integrity of the somatosensory nervous system. Over the years, different protocols have been established, which utilize similar but distinct testing procedures. They pursue the same overall objective to identify loss or gain of function of the respective sensory parameter to better understand the degree of abnormal nervous function and thereby improve patient care in the long-term. Laboratory-based QST protocols, which apply highly standardized testing procedures in pre-defined order and body regions, are considered as the gold standard in sensory testing. However, those protocols often require specifically trained personal, high equipment investment, and are time consuming. Thus, in recent years several attempts have been made to simplify testing protocols as well as reduce high costs of testing equipment such as thermal probe systems. These attempts have culminated in an array of sensory bedside testing protocols subserving the need for protocols that are easy to implement in and provide a standardized assessment within clinical trials. While laboratory and bedside QST that focus on static responses of single stimuli, protocols for testing dynamic QST focus on the functional response to pain also exist. Conditioned pain modulation (CPM) is often applied, which offers the ability to study endogenous inhibition of pain. All of these mentioned methodologies are considered as psychophysical measures and thus rely heavily on the cooperation of the patient or participant. In this chapter we provide an overview of QST along three main lines: (i) laboratory QST, (ii) bedside QST and (iii) dynamic QST. In addition, we discuss advantages and pitfalls of each modality. While we discuss along these lines, it should be noted that methodologies are overlapping: some bedside tests are similar or identical to lab-QST, many lab-QST protocols include a dynamic component, and assessment of dynamic QST requires to start with static assessments.
Neuromodulation for neuropathic pain.
da Cunha PHM, Lapa JDDS, Hosomi K … +1 more , de Andrade DC
Int Rev Neurobiol · 2024 · PMID 39580221 · Publisher ↗
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 i...
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.
Psychological, physical and complementary therapies for the management of neuropathic pain.
Norman-Nott N, Cashin AG, Gustin SM
Int Rev Neurobiol · 2024 · PMID 39580220 · Publisher ↗
This chapter aims to explain and evaluate the evidence for psychological, physical and complementary therapies as part of a holistic plan for managing neuropathic pain. Psychological therapies refer to interventions targ...
This chapter aims to explain and evaluate the evidence for psychological, physical and complementary therapies as part of a holistic plan for managing neuropathic pain. Psychological therapies refer to interventions targeting mental health, while physical therapies refer to interventions designed to target movement and functional ability, and complementary therapies are those that attempt to target key mechanisms of change to alter brain and body functioning, or thought processes related to the experience of pain. Each therapeutic modality is discussed to narratively report on the evidence and provide implications for clinicians. Where evidence was unavailable for neuropathic pain populations, evidence from chronic pain populations more broadly was considered. Although promising, there is a lack of high-quality evidence investigating the benefits and safety of psychological, physical and complementary therapies for the management of neuropathic pain. The low certainty evidence and lack of evidence across different neuropathic pain conditions impacts the ability to make recommendations for clinical practice. However, there are several potential areas for future research. Psychological therapies that focus on the underlying mechanisms related to emotion regulation may improve mood and pain, while cognitive and behavioural based approaches may improve psychological comorbidities such as anxiety and depression. Physical therapies involving physical activity and exercise, education, and graded motor imagery may improve functioning and reduce pain. Finally, complementary therapies including electroencephalography neurofeedback, acupuncture, virtual reality, hypnosis and transcutaneous electrical nerve stimulation may provide promising reductions in pain. There is a clear need for further high-quality trials to evaluate the benefits and safety of psychological, physical and complementary therapies to guide the management of neuropathic pain.
Neuropathic pain - A clinical primer.
Jan Rosner, Shirvalkar P, de Andrade DC
Int Rev Neurobiol · 2024 · PMID 39580219 · Publisher ↗
Neuropathic pain is used both as a mechanistic descriptor and a classification category of pain caused by a lesion or disease of the somatosensory nervous system and encompasses a vast array of possible diagnoses. The id...
Neuropathic pain is used both as a mechanistic descriptor and a classification category of pain caused by a lesion or disease of the somatosensory nervous system and encompasses a vast array of possible diagnoses. The identification of neuropathic pain and diagnosis of specific syndromes relies on a detailed patient history. Standardized pain questionnaires can capture the patient`s symptoms, while the anatomical distribution of pain is often documented using pain drawings. Following this, a thorough clinical neurological examination is conducted to identify distinct sensory abnormalities, specifically sensory deficits and signs of increased sensitivity such as allodynia and hyperalgesia, within the pain-affected areas. Regardless of whether the lesion or disease is in the peripheral or central somatosensory nervous system, the presence of clinically overt sensory abnormalities is a key feature, distinguishing neuropathic pain from other types of pain, such as nociceptive pain, which likely coexist in neurological disorders. Extensive sensory deficits, as seen in certain stroke syndromes or following spinal cord injuries, may increase the likelihood of concomitant non-neuropathic pain within the same area of sensory loss. For this reason, differential diagnosis is essential when assessing patients with suspected neuropathic pain. Further diagnostic tests, including imaging or specific neurophysiological methods that assess nociceptive pathways, can provide objective evidence of a lesion or disease within the somatosensory nervous system. However, the causality between the lesion and the presence of neuropathic pain cannot be established definitively and always requires clinical judgment and interpretation within the broader context of the neurological disorder.
Clinical pharmacology of neuropathic pain.
Rosner J, Attal N, Finnerup NB
Int Rev Neurobiol · 2024 · PMID 39580218 · Publisher ↗
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 condition...
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.
Animal models of neuropathic pain.
Casaril AM, Gaffney CM, Shepherd AJ
Int Rev Neurobiol · 2024 · PMID 39580217 · Publisher ↗
Animal models continue to be crucial to developing our understanding of the molecular, cellular, and neurophysiological mechanisms that lead to neuropathic pain. The overwhelming majority of animal studies use rodent mod...
Animal models continue to be crucial to developing our understanding of the molecular, cellular, and neurophysiological mechanisms that lead to neuropathic pain. The overwhelming majority of animal studies use rodent models, ranging from surgical and trauma-induced models to those induced by metabolic diseases, genetic mutations, viruses, neurotoxic drugs, and cancer. We discuss the clinical relevance of the available models and the pain behavior tests commonly used as outcome measures. Finally, we summarize the refinements that have been proposed to improve the ability of animal model studies to predict clinical efficacy.
Exploring neuroinflammation: A key driver in neuropathic pain disorders.
Scheuren PS, Calvo M
Int Rev Neurobiol · 2024 · PMID 39580216 · Publisher ↗
Inflammation is a fundamental part of the body's natural defense mechanism, involving immune cells and inflammatory mediators to promote healing and protect against harm. In the event of a lesion or disease of the somato...
Inflammation is a fundamental part of the body's natural defense mechanism, involving immune cells and inflammatory mediators to promote healing and protect against harm. In the event of a lesion or disease of the somatosensory nervous system, inflammation, however, triggers a cascade of changes in both the peripheral and central nervous systems, ultimately contributing to chronic neuropathic pain. Substantial evidence links neuroinflammation to various conditions associated with neuropathic pain. This chapter will explore the role of neuroinflammation in the initiation, maintenance, and resolution of peripheral and central neuropathic pain. Additionally, biomarkers of neuroinflammation in humans will be examined, emphasizing their relevance in different neuropathic pain disorders.
Molecular mechanisms of neuropathic pain.
Pacifico P, Menichella DM
Int Rev Neurobiol · 2024 · PMID 39580215 · Publisher ↗
Peripheral neuropathic pain, which occurs after a lesion or disease affecting the peripheral somatosensory nervous system, is a complex and challenging condition to treat. This chapter will cover molecular mechanisms und...
Peripheral neuropathic pain, which occurs after a lesion or disease affecting the peripheral somatosensory nervous system, is a complex and challenging condition to treat. This chapter will cover molecular mechanisms underlying the pathophysiology of peripheral neuropathic pain, focusing on (1) sensitization of nociceptors, (2) neuro-immune crosstalk, and (3) axonal degeneration and regeneration. The chapter will also emphasize the importance of identifying novel therapeutic targets in non-neuronal cells. A comprehensive understanding of how changes at both neuronal and non-neuronal levels contribute to peripheral neuropathic pain may significantly improve pain management and treatment options, expanding to topical application that bypass the side effects associated with systemic administration.
Modeling neuropathic pain in a dish.
Zebochin I, Denk F, Nochi Z
Int Rev Neurobiol · 2024 · PMID 39580214 · Publisher ↗
The study of pain mechanisms has advanced significantly with the development of innovative in vitro models. This chapter explores those already used in or potentially useful for neuropathic pain research, emphasizing the...
The study of pain mechanisms has advanced significantly with the development of innovative in vitro models. This chapter explores those already used in or potentially useful for neuropathic pain research, emphasizing the complementary roles of animal and human cellular models to enhance translational success. Traditional animal models have provided foundational insights into the neurobiology of pain and remain invaluable for understanding complex pain pathways. However, integrating human cellular models addresses the need for better replication of human nociceptors. The chapter details methodologies for culturing rodent and human primary sensory neurons, including isolation and culture techniques, advantages, and limitations. It highlights the application of these models in neuropathic pain research, such as identifying pain-associated receptors and ion channels. Recent advancements in using induced pluripotent stem cell (iPSC)-derived sensory neurons are also discussed. Finally, the chapter explores advanced in vitro models, including 2D co-cultures and 3D organoids, and their implications for studying neuropathic pain. These models offer significant advantages for drug screening and ethical research practices, providing a more accurate representation of human pain pathways and paving the way for innovative therapeutic strategies. Despite challenges such as limited access to viable human tissue and variability between samples, these in vitro models, alongside traditional animal models, are indispensable for advancing our understanding of neuropathic pain and developing effective treatments.
Small fiber neuropathy.
Kool D, Hoeijmakers JG, Waxman SG … +1 more , Faber CG
Int Rev Neurobiol · 2024 · PMID 39580213 · Publisher ↗
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...
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.
Placebo effects in neuropathic pain conditions.
Kothari SF, Emborg C, Vase L
Int Rev Neurobiol · 2024 · PMID 39580212 · Publisher ↗
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 pla...
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.
Clinical neurophysiology of neuropathic pain.
Hubli M, Leone C
Int Rev Neurobiol · 2024 · PMID 39580211 · Publisher ↗
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 objec...
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.
Neuroanatomy of the nociceptive system: From nociceptors to brain networks.
Motzkin JC, Basbaum AI, Crowther AJ
Int Rev Neurobiol · 2024 · PMID 39580210 · Full text
This chapter reviews the neuroanatomy of the nociceptive system and its functional organization. We describe three main compartments of the nervous system that underlie normal nociception and the resulting pain percept:...
This chapter reviews the neuroanatomy of the nociceptive system and its functional organization. We describe three main compartments of the nervous system that underlie normal nociception and the resulting pain percept: Peripheral, Spinal Cord, and Brain. We focus on how ascending nociceptive processing streams traverse these anatomical compartments, culminating in the multidimensional experience of pain. We also describe neuropathic pain conditions, in which nociceptive processing is abnormal, not only because of the primary effects of a lesion or disease affecting peripheral nerves or the central nervous system (CNS), but also due to secondary effects on ascending pathways and brain networks. We discuss how the anatomical components (circuits/networks) reorganize under various etiologies of neuropathic pain and how these changes can give rise to pathological pain states.
Preface.
Camarini R, Cruz FC
Int Rev Neurobiol · 2024 · PMID 39523065 · Publisher ↗
Abstract loading — click title to view on PubMed.
The CRF/Urocortin systems as therapeutic targets for alcohol use disorders.
Favoretto CA, Bertagna NB, Miguel TT … +1 more , Quadros IMH
Int Rev Neurobiol · 2024 · PMID 39523064 · Publisher ↗
Development and maintenance of alcohol use disorders have been proposed to recruit critical mechanisms involving Corticotropin Releasing Factor and Urocortins (CRF/Ucns). The CRF/Ucns system is comprised of a family of p...
Development and maintenance of alcohol use disorders have been proposed to recruit critical mechanisms involving Corticotropin Releasing Factor and Urocortins (CRF/Ucns). The CRF/Ucns system is comprised of a family of peptides (CRF, Ucn 1, Ucn 2, Ucn 3) which act upon two receptor subtypes, CRFR1 and CRFR2, each with different affinity profiles to the endogenous peptides and differential brain distribution. Activity of CRF/Ucn system is further modulated by CRF binding protein (CRF-BP), which regulates availability of CRF and Ucns to exert their actions. Extensive evidence in preclinical models support the involvement of CRF/Ucn targets in escalated alcohol drinking, as well as point to changes in CRF/Ucn brain function as a result of chronic alcohol exposure and/or withdrawal. It highlights the role of CRF and CRFR1-mediated signaling in conditions of excessive alcohol taking and seeking, including during various stages of withdrawal and relapse to alcohol. Besides its role in the hypothalamic-pituitary-adrenal (HPA) axis, the importance of extra-hypothalamic CRF pathways, especially in the extended amygdala, in the neurobiology of alcohol abuse and dependence is emphasized. Emerging roles for other targets of the CRF/Ucn system, such as CRF2 receptors, CRF-BP and Ucns in escalated alcohol drinking is also discussed. Finally, the limited translational value of CRF/Ucn interventions in stress-related and alcohol use disorders is discussed. So far, CRFR1 antagonists have shown little or no efficacy in human clinical trials, although a range of unexplored conditions and possibilities remain to be explored.
Emerging evidence for pregnane steroid therapeutics for alcohol use disorders.
Morrow AL, McFarland MH, O'Buckley TK … +1 more , Robinson DL
Int Rev Neurobiol · 2024 · PMID 39523063 · Publisher ↗
Many lines of research have suggested that the neuroactive pregnane steroids, including pregnenolone, progesterone, and allopregnanolone ([3α,5α]-3-hydroxypregnan-20-one, 3α,5α-THP), have therapeutic potential for treatm...
Many lines of research have suggested that the neuroactive pregnane steroids, including pregnenolone, progesterone, and allopregnanolone ([3α,5α]-3-hydroxypregnan-20-one, 3α,5α-THP), have therapeutic potential for treatment of alcohol use disorders (AUDs). In this chapter, we systematically address the preclinical and clinical evidence that supports this approach for AUD treatment, describe the underlying neurobiology of AUDs that are targeted by these treatments, and delineate how pregnane steroids may address various components of the disease. This review updates the theoretical framework for understanding how endogenous steroids that modulate the effects of alcohol, stress, excitatory/inhibitory and dopamine transmission, and the innate immune system appear to play a key role in the prevention and mitigation of AUDs. We further discuss newly discovered limitations of pregnane steroid therapies as well as the challenges that are inherent to development of endogenous compounds for therapeutics. We argue that overcoming these challenges presents the opportunity to help millions who suffer from AUDs across the world.
Ghrelin system and GLP-1 as potential treatment targets for alcohol use disorder.
Jerlhag E
Int Rev Neurobiol · 2024 · PMID 39523062 · Publisher ↗
Peptides of the gut-brain axis have gained recent attention as potential treatment targets for addiction. While the number of gut-brain peptides is vast, ghrelin and glucagon-like peptide-1 (GLP-1) have been suggested as...
Peptides of the gut-brain axis have gained recent attention as potential treatment targets for addiction. While the number of gut-brain peptides is vast, ghrelin and glucagon-like peptide-1 (GLP-1) have been suggested as important players. Ghrelin is traditionally considered an orexigenic peptide, but recent studies found that it increases alcohol intake in rodents and craving for alcohol in humans. Additionally, suppression of the ghrelin receptor attenuates alcohol-related responses in animal models reflecting alcohol use disorder (AUD). For instance, a lower alcohol intake, suppressed motivation to consume alcohol, and attenuated reward from alcohol is observed after ghrelin receptor antagonism treatment. On a similar note, a partial ghrelin receptor agonist prevents hangover symptoms in humans. When it comes to the anorexigenic peptide GLP-1, agonists of its receptor are approved to treat diabetes type 2 and obesity. Extensive preclinical studies have revealed that these GLP-1 receptor agonists reduce alcohol intake, suppress the motivation to consume alcohol, and prevent relapse drink, with effects tentatively associated with a reduced alcohol-induced reward. These preclinical findings have to some extent been varied in humans, as GLP-1 receptor agonists decrease alcohol intake in overweight patients with AUD. Furthermore, genetic variations in either the genes encoding for pre-pro-ghrelin, GHSR, GLP-1, or its receptor, are associated with AUD and heavy alcohol drinking. While central mechanisms appear to modulate the ability of either ghrelin or GLP-1 to regulate alcohol-related responses the exact mechanisms have not been defined. Taken together these preclinical and clinical data imply that gut-brain peptides participate in the addiction process and should be considered as potential targets for AUD treatment.
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