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Publications | Hebrew University Center for Research on Pain

Publications

2023
Yanko, Robert et al. Exploring The Effect Of Ethnicity On Chronic Orofacial Pain: A Comparative Study Of Jewish And Arab Israeli Patients. Healthcare (Basel) 11.14 (2023). Web.Abstract

The relationship between ethnicity and chronic pain has been studied worldwide. The population of Israel includes two main ethnic groups, 75% Jews and 21% Arabs. The purpose of this study was to compare orofacial chronic pain characteristics and treatment outcomes between Jewish and Arab Israeli citizens. Two hundred patients admitted to the Orofacial Pain Clinic at Hebrew University-Hadassah School of Dental Medicine between 2017 and 2022 were selected randomly for this historical cohort study. Our cohort included 159 (79.5%) Jews and 41 (20.5%) Arabs. Twenty-six pain-related variables were compared of which only two differed significantly between the two groups, awakening due to pain and mean muscle sensitivity; both indicators were higher in the Arab group ( < 0.05). No differences were found in any of the other variables such as diagnosis, pain severity, onset, and treatment outcome. This minimal difference may be explained by the equal accessibility to medical services for all citizens, and the diversity of our staff that includes Jew as well as Arab service providers. These factors minimize or even eliminate racial bias, language, and cultural barriers, and is reflected in the minor differences in orofacial pain characteristics found between the two main ethnic groups in Israel.

Almoznino, Galit et al. Migraine Prevalence, Burden, And Socio-Demographic Characteristics Globally And In Israel: A Narrative Review. Isr Med Assoc J 25.9 (2023): 639-643. Print.
Almoznino, Galit et al. Olfactory And Gustatory Disorders Associated With Sars-Cov-2 Infection In Children And Adults: A Topic Review. Quintessence Int 54.10 (2023): 852-866. Web.Abstract

This paper is aimed at comprehensively reviewing olfactory and gustatory disorders caused by SARS-CoV-2 in children and adults. An electronic and manual search was done on three databases: MEDLINE, Embase, and Web of Science. Inclusion criteria included publications written in English, involving humans in the age range of 0 to 99 years that were captured by a controlled vocabulary of thesaurus terms. Olfactory and gustatory disorders rates in COVID-19 ranged from 22% to 71.9% in adults and 16.6% to 25.8% in children. Olfactory and gustatory disorders might appear as the first symptom, and in adults might even be the only symptom (4.8% to 10%). Anosmia is the most common olfactory disorder and hypogeusia is the most common gustatory disorder. In 33% to 89% of cases, olfactory and gustatory disorders resolve spontaneously within a few weeks, coinciding with the resolution of other COVID-19 symptoms, both in adults and children. However, in some patients, olfactory and gustatory disorders persist beyond the resolution of other symptoms. Notably, children generally experience a swifter and more favorable recovery compared to adults. The precise pathogenesis underlying olfactory and gustatory disorders in the context of COVID-19 remains unclear and is likely multifactorial. Presently, no established treatment protocol exists for olfactory and gustatory disorders and current treatments reviewed lack robust evidence and are not readily available for clinical use. Olfactory training represents the only therapy currently recommended by international authorities. Pediatric practitioners and general dental practitioners should be aware of olfactory and gustatory disorders in both pediatric and adult populations, including their biologic mechanisms, treatment options, and recovery rates.

Heiliczer, Shimrit et al. Oxidative Stress-Mediated Proapoptosis Signaling: A Novel Theory On The Mechanism Underlying The Pathogenesis Of Burning Mouth Syndrome. J Am Dent Assoc (2023). Web.Abstract

BACKGROUND: Burning mouth syndrome (BMS) is a chronic oral pain disorder characterized by a generalized burning sensation in the oral mucosa without apparent medical or dental causes. Despite various hypotheses proposed to explain BMS pathogenesis, a clear understanding of the cellular-level events and associated histologic and molecular findings is lacking. Advancing our understanding of BMS pathogenesis could facilitate the development of more targeted therapeutic interventions.

TYPES OF STUDIES REVIEWED: The authors conducted an extensive literature search and review of cellular mechanisms, focusing on evidence-based data that support a comprehensive hypothesis for BMS pathogenesis. The authors explored novel and detailed mechanisms that may account for the characteristic features of BMS.

RESULTS: The authors proposed that BMS symptoms arise from the uncontrolled activation of proapoptotic transmembrane calcium permeable channels expressed in intraoral mucosal nerve fibers. Elevated levels of reactive oxygen species or dysfunctional antiapoptosis pathways may lead to uncontrolled oxidative stress-mediated apoptosis signaling, resulting in upregulation of transmembrane transient receptor potential vanilloid type 1 and P2X 3 calcium channels in nociceptive fibers. Activation of these channels can cause nerve terminal depolarization, leading to generation of action potentials that are centrally interpreted as pain.

CONCLUSIONS AND PRACTICAL IMPLICATIONS: The authors present a novel hypothesis for BMS pathogenesis, highlighting the role of proapoptotic transmembrane calcium permeable channels and oxidative stress-mediated apoptosis signaling in the development of BMS symptoms. Understanding these underlying mechanisms could provide new insights into the development of targeted therapeutic interventions for BMS. Additional research is warranted to validate this hypothesis and explore potential avenues for effective management of BMS.

Aizenbud, Itay, Asaf Wilensky, and Galit Almoznino. Periodontal Disease And Its Association With Metabolic Syndrome-A Comprehensive Review. Int J Mol Sci 24.16 (2023). Web.Abstract

Periodontal disease is a complex and progressive chronic inflammatory condition that leads to the loss of alveolar bone and teeth. It has been associated with various systemic diseases, including diabetes mellitus and obesity, among others. Some of these conditions are part of the metabolic syndrome cluster, a group of interconnected systemic diseases that significantly raise the risk of cardiovascular diseases, diabetes mellitus, and stroke. The metabolic syndrome cluster encompasses central obesity, dyslipidemia, insulin resistance, and hypertension. In this review, our objective is to investigate the correlation between periodontal disease and the components and outcomes of the metabolic syndrome cluster. By doing so, we aim to gain insights into the fundamental mechanisms that link each systemic condition with the metabolic syndrome. This deeper understanding of the interplay between these conditions and periodontal disease can pave the way for more effective treatments that take into account the broader impact of managing periodontal disease on the comprehensive treatment of systemic diseases, and vice versa.

Gitik, Miri et al. Deletion Of Cd47 From Schwann Cells And Macrophages Hastens Myelin Disruption/Dismantling And Scavenging In Schwann Cells And Augments Myelin Debris Phagocytosis In Macrophages. J Neuroinflammation 20.1 (2023): 243. Web.Abstract

BACKGROUND: Myelin that surrounds axons breaks in trauma and disease; e.g., peripheral nerve and spinal cord injuries (PNI and SCI) and multiple sclerosis (MS). Resulting myelin debris hinders repair if not effectively scavenged by Schwann cells and macrophages in PNI and by microglia in SCI and MS. We showed previously that myelin debris evades phagocytosis as CD47 on myelin ligates SIRPα (signal regulatory protein-α) on macrophages and microglia, triggering SIRPα to inhibit phagocytosis in phagocytes. Using PNI as a model, we tested the in vivo significance of SIRPα-dependent phagocytosis inhibition in SIRPα null mice, showing that SIRPα deletion leads to accelerated myelin debris clearance, axon regeneration and recovery of function from PNI. Herein, we tested how deletion of CD47, a SIRPα ligand and a cell surface receptor on Schwann cells and phagocytes, affects recovery from PNI.

METHODS: Using CD47 null (CD47-/-) and wild type mice, we studied myelin disruption/dismantling and debris clearance, axon regeneration and recovery of function from PNI.

RESULTS: As expected from CD47 on myelin acting as a SIRPα ligand that normally triggers SIRPα-dependent phagocytosis inhibition in phagocytes, myelin debris clearance, axon regeneration and function recovery were all faster in CD47-/- mice than in wild type mice. Unexpectedly compared with wild type mice, myelin debris clearance started sooner and CD47-deleted Schwann cells displayed enhanced disruption/dismantling and scavenging of myelin in CD47-/- mice. Furthermore, CD47-deleted macrophages from CD47-/- mice phagocytosed more myelin debris than CD47-expressing phagocytes from wild type mice.

CONCLUSIONS: This study reveals two novel normally occurring CD47-dependent mechanisms that impede myelin debris clearance. First, CD47 expressed on Schwann cells inhibits myelin disruption/dismantling and debris scavenging in Schwann cells. Second, CD47 expressed on macrophages inhibits myelin debris phagocytosis in phagocytes. The two add to a third mechanism that we previously documented whereby CD47 on myelin ligates SIRPα on macrophages and microglia, triggering SIRPα-dependent phagocytosis inhibition in phagocytes. Thus, CD47 plays multiple inhibitory roles that combined impede myelin debris clearance, leading to delayed recovery from PNI. Similar inhibitory roles in microglia may hinder recovery from other pathologies in which repair depends on efficient phagocytosis (e.g., SCI and MS).

Tal, Michael, Anne Minert, and Marshall Devor. Resurgent Neuropathic Discharge: An Obstacle To The Therapeutic Use Of Neuroma Resection?. Pain 164.2 (2023): 349-361. Web.Abstract

Ectopic discharge ("ectopia") in damaged afferent axons is a major contributor to chronic neuropathic pain. Clinical opinion discourages surgical resection of nerves proximal to the original injury site for fear of resurgence of ectopia and exacerbated pain. We tested this concept in a well-established animal neuroma model. Teased-fiber recordings were made of ectopic spontaneous discharge originating in the experimental nerve-end neuroma and associated dorsal root ganglia in rats that underwent either a single transection (with ligation) of the sciatic nerve or 2 consecutive transections separated by 7, 14, 21, or 30 days. Ectopia emerged in afferent A and C fibers after a single cut with kinetics anticipated from previous studies. When resection was performed during the early period of intense A-fiber activity, a brief period of resurgence was observed. However, resection of neuromas of more than 14 days was followed by low levels of activity with no indication of resurgence. This remained the case in trials out to 60 days after the first cut. Similarly, we saw no indication of resurgent ectopia originating in axotomized dorsal root ganglion neuronal somata and no behavioral reflection of resurgence. In summary, we failed to validate the concern that proximal resection of a problematic nerve would lead to intense resurgent ectopic discharge and pain. As the well-entrenched concept of resurgence is based more on case reports and anecdotes than on solid evidence, it may be justified to relax the stricture against resecting neuromas as a therapeutic strategy, at least within the framework of controlled clinical trials.

Raz, Noa et al. Selected Cannabis Terpenes Synergize With Thc To Produce Increased Cb1 Receptor Activation. Biochem Pharmacol 212 (2023): 115548. Web.Abstract

The cannabis plant exerts its pharmaceutical activity primarily by the binding of cannabinoids to two G protein-coupled cannabinoid receptors, CB1 and CB2. The role that cannabis terpenes play in this activation has been considered and debated repeatedly, based on only limited experimental results. In the current study we used a controlled in-vitro heterologous expression system to quantify the activation of CB1 receptors by sixteen cannabis terpenes individually, by tetrahydrocannabinol (THC) alone and by THC-terpenes mixtures. The results demonstrate that all terpenes, when tested individually, activate CB1 receptors, at about 10-50% of the activation by THC alone. The combination of some of these terpenes with THC significantly increases the activity of the CB1 receptor, compared to THC alone. In some cases, several fold. Importantly, this amplification is evident at terpene to THC ratios similar to those in the cannabis plant, which reflect very low terpene concentrations. For some terpenes, the activation obtained by THC- terpene mixtures is notably greater than the sum of the activations by the individual components, suggesting a synergistic effect. Our results strongly support a modulatory effect of some of the terpenes on the interaction between THC and the CB1 receptor. As the most effective terpenes are not necessarily the most abundant ones in the cannabis plant, reaching "whole plant" or "full spectrum" composition is not necessarily an advantage. For enhanced therapeutic effects, desired compositions are attainable by enriching extracts with selected terpenes. These compositions adjust the treatment for various desired medicinal and personal needs.

Eyal, Aharon M et al. Vapor Pressure, Vaping, And Corrections To Misconceptions Related To Medical Cannabis' Active Pharmaceutical Ingredients' Physical Properties And Compositions. Cannabis Cannabinoid Res 8.3 (2023): 414-425. Web.Abstract

Medical cannabis products contain dozens of active pharmaceutical ingredients (APIs) derived from the cannabis plant. However, their actual compositions and relative doses significantly change according to the production methods. Product compositions are strongly dependent on processing step conditions and on components' evaporation during those steps. Review of the documentation presented to caregivers and to patients show erroneous data or misinterpretation of data related to the evaporation, for example, cannabinoids' boiling points, as well as confusions between terms, such as boiling, vaporization, and evaporation. Clarifying these aspects is essential for caregivers, for researchers, and for developers of manufacturing processes. Original and literature data were analyzed, comparing composition changes during various processing steps and correlating the extent of change to components' vapor pressures at the corresponding temperature. Evaporation-related composition changes start at temperatures as low as those of drying and curing and become extensive during decarboxylation. The relative rate of components' evaporation is determined by their relative vapor pressure and monoterpenes are lost first. On vaping, terpenes are inhaled before cannabinoids do. Commercial medical cannabis products are deficient in terpenes, mainly monoterpenes, compared with the cannabis plants used to produce them. Terms, such as "whole plant" and "full spectrum," are misleading since no product actually reflects the original cannabis plant composition. There are important implications for medical cannabis manufacturing and for the ability to make the most out of the terpene API contribution. Medical cannabis products' composition and product delivery are controlled by the relative vapor pressure of the various APIs. Quantitative data provided in this study can be used for improvement to reach better accuracy, reproducibility, and preferred medical cannabis compositions.

Rayi, Prudhvi Raj, Shaya Lev, and Alexander M Binshtok. Age-Dependent Decrease In Inhibitory Drive On The Excitatory Superficial Spinal Dorsal Horn Neurons. Neurobiol Pain 14 (2023): 100139. Web.Abstract

The excitatory and inhibitory interneurons of superficial laminae I-II of the spinal dorsal horn (SDH) receive and process pain-related information from the primary afferents and transmit it to the brain via the projection neurons. Thus, the interaction between excitatory and inhibitory SDH interneurons is crucial in determining the output from the spinal cord network. Disruption of this interaction in pathological conditions leads to increased SDH output to the higher brain centers, which could underlie pathological pain. Here, we examined whether the changes in the intrinsic SDH connectivity also occur with age, possibly underlying age-related increase in pain sensitivity. Using transgenic mouse line, we compared the spontaneous inhibitory postsynaptic currents (sIPSCs) in inhibitory tdTomato and excitatory tdTomato interneurons between adult (3-5 m.o.) and aged (12-13 m.o.) mice. We demonstrate that in adult mice, the amplitude and frequency of the sIPSCs on the excitatory interneurons were significantly higher than on inhibitory interneurons. These differences were annulled in aged mice. Further, we show that in aged mice, excitatory neurons receive less inhibition than in adult mice. This could lead to overall disinhibition of the SDH network, which might underlie increased pain perception among the aged population.

Barkai, Omer et al. Encoding Of Inflammatory Hyperalgesia In Mouse Spinal Cord. Pain 164.2 (2023): 443-460. Web.Abstract

Inflammation modifies the input-output properties of peripheral nociceptive neurons such that the same stimulus produces enhanced nociceptive firing. This increased nociceptive output enters the superficial dorsal spinal cord (SDH), an intricate neuronal network composed largely of excitatory and inhibitory interneurons and a small percentage of projection neurons. The SDH network comprises the first central nervous system network integrating noxious information. Using in vivo calcium imaging and a computational approach, we characterized the responsiveness of the SDH network in mice to noxious stimuli in normal conditions and investigated the changes in SDH response patterns after acute burn injury-induced inflammation. We show that the application of noxious heat stimuli to the hind paw of naïve mice results in an overall increase in SDH network activity. Single-cell response analysis reveals that 70% of recorded neurons increase or suppress their activity, while ∼30% of neurons remain nonresponsive. After acute burn injury and the development of inflammatory hyperalgesia, application of the same noxious heat stimuli leads to the activation of previously nonresponding neurons and desuppression of suppressed neurons. We further demonstrate that an increase in afferent activity mimics the response of the SDH network to noxious heat stimuli under inflammatory conditions. Using a computational model of the SDH network, we predict that the changes in SDH network activity result in overall increased activity of excitatory neurons, amplifying the output from SDH to higher brain centers. We suggest that during acute local peripheral inflammation, the SDH network undergoes dynamic changes promoting hyperalgesia.

Baron, Mark, and Marshall Devor. From Molecule To Oblivion: Dedicated Brain Circuitry Underlies Anesthetic Loss Of Consciousness Permitting Pain-Free Surgery. Front Mol Neurosci 16 (2023): 1197304. Web.Abstract

The canonical view of how general anesthetics induce loss-of-consciousness (LOC) permitting pain-free surgery posits that anesthetic molecules, distributed throughout the CNS, suppress neural activity globally to levels at which the cerebral cortex can no longer sustain conscious experience. We support an alternative view that LOC, in the context of GABAergic anesthesia at least, results from anesthetic exposure of a small number of neurons in a focal brainstem nucleus, the mesopontine tegmental anesthesia area (MPTA). The various sub-components of anesthesia, in turn, are effected in distant locations, driven by dedicated axonal pathways. This proposal is based on the observations that microinjection of infinitesimal amounts of GABAergic agents into the MPTA, and only there, rapidly induces LOC, and that lesioning the MPTA renders animals relatively insensitive to these agents delivered systemically. Recently, using chemogenetics, we identified a subpopulation of MPTA "effector-neurons" which, when excited (not inhibited), induce anesthesia. These neurons contribute to well-defined ascending and descending axonal pathways each of which accesses a target region associated with a key anesthetic endpoint: atonia, anti-nociception, amnesia and LOC (by electroencephalographic criteria). Interestingly, the effector-neurons do not themselves express GABA-receptors. Rather, the target receptors reside on a separate sub-population of presumed inhibitory interneurons. These are thought to excite the effectors by disinhibition, thus triggering anesthetic LOC.

Dey, Swagata et al. Kinesin Family Member 2A Gates Nociception. Cell Rep 42.10 (2023): 113257. Web.Abstract

Nociceptive axons undergo remodeling as they innervate their targets during development and in response to environmental insults and pathological conditions. How is nociceptive morphogenesis regulated? Here, we show that the microtubule destabilizer kinesin family member 2A (Kif2a) is a key regulator of nociceptive terminal structures and pain sensitivity. Ablation of Kif2a in sensory neurons causes hyperinnervation and hypersensitivity to noxious stimuli in young adult mice, whereas touch sensitivity and proprioception remain unaffected. Computational modeling predicts that structural remodeling is sufficient to explain the phenotypes. Furthermore, Kif2a deficiency triggers a transcriptional response comprising sustained upregulation of injury-related genes and homeostatic downregulation of highly specific channels and receptors at the late stage. The latter effect can be predicted to relieve the hyperexcitability of nociceptive neurons, despite persisting morphological aberrations, and indeed correlates with the resolution of pain hypersensitivity. Overall, we reveal a critical control node defining nociceptive terminal structure, which is regulating nociception.

Katz, Ben et al. Nociception And Pain In Humans Lacking A Functional Trpv1 Channel. J Clin Invest 133.3 (2023). Web.Abstract

BACKGROUNDChronic pain is a debilitating illness with currently limited therapy, in part due to difficulties in translating treatments derived from animal models to patients. The transient receptor potential vanilloid 1 (TRPV1) channel is associated with noxious heat detection and inflammatory pain, and reports of adverse effects in human trials have hindered extensive efforts in the clinical development of TRPV1 antagonists as novel pain relievers.METHODSWe examined 2 affected individuals (A1 and A2) carrying a homozygous missense mutation in TRPV1, rendering the channel nonfunctional. Biochemical and functional assays were used to analyze the mutant channel. To identify possible phenotypes of the affected individuals, we performed psychophysical and medical examinations.RESULTSWe demonstrated that diverse TRPV1 activators, acting at different sites of the channel protein, were unable to open the cloned mutant channel. This finding was not a consequence of impairment in the expression, cellular trafficking, or assembly of protein subunits. The affected individuals were insensitive to application of capsaicin to the mouth and skin and did not demonstrate aversive behavior toward capsaicin. Furthermore, quantitative sensory testing of A1 revealed an elevated heat-pain threshold but also, surprisingly, an elevated cold-pain threshold and extensive neurogenic inflammatory, flare, and pain responses following application of the TRPA1 channel activator mustard oil.CONCLUSIONOur study provides direct evidence in humans for pain-related functional changes linked to TRPV1, which is a prime target in the development of pain relievers.FUNDINGSupported by the Israel Science Foundation (368/19); Teva's National Network of Excellence in Neuroscience grant (no. 0394886) and Teva's National Network of Excellence in Neuroscience postdoctoral fellowship.

Caspi, Yaki et al. Structural Plasticity Of Axon Initial Segment In Spinal Cord Neurons Underlies Inflammatory Pain. Pain 164.6 (2023): 1388-1401. Web.Abstract

Physiological or pathology-mediated changes in neuronal activity trigger structural plasticity of the action potential generation site-the axon initial segment (AIS). These changes affect intrinsic neuronal excitability, thus tuning neuronal and overall network output. Using behavioral, immunohistochemical, electrophysiological, and computational approaches, we characterized inflammation-related AIS plasticity in rat's superficial (lamina II) spinal cord dorsal horn (SDH) neurons and established how AIS plasticity regulates the activity of SDH neurons, thus contributing to pain hypersensitivity. We show that in naive conditions, AIS in SDH inhibitory neurons is located closer to the soma than in excitatory neurons. Shortly after inducing inflammation, when the inflammatory hyperalgesia is at its peak, AIS in inhibitory neurons is shifted distally away from the soma. The shift in AIS location is accompanied by the decrease in excitability of SDH inhibitory neurons. These AIS location and excitability changes are selective for inhibitory neurons and reversible. We show that AIS shift back close to the soma, and SDH inhibitory neurons' excitability increases to baseline levels following recovery from inflammatory hyperalgesia. The computational model of SDH inhibitory neurons predicts that the distal shift of AIS is sufficient to decrease the intrinsic excitability of these neurons. Our results provide evidence of inflammatory pain-mediated AIS plasticity in the central nervous system, which differentially affects the excitability of inhibitory SDH neurons and contributes to inflammatory hyperalgesia.

2022
Weber, Kenneth A et al. Confounds In Neuroimaging: A Clear Case Of Sex As A Confound In Brain-Based Prediction. Front Neurol 13 (2022): 960760. Web.Abstract

Muscle weakness is common in many neurological, neuromuscular, and musculoskeletal conditions. Muscle size only partially explains muscle strength as adaptions within the nervous system also contribute to strength. Brain-based biomarkers of neuromuscular function could provide diagnostic, prognostic, and predictive value in treating these disorders. Therefore, we sought to characterize and quantify the brain's contribution to strength by developing multimodal MRI pipelines to predict grip strength. However, the prediction of strength was not straightforward, and we present a case of sex being a clear confound in brain decoding analyses. While each MRI modality-structural MRI (i.e., gray matter morphometry), diffusion MRI (i.e., white matter fractional anisotropy), resting state functional MRI (i.e., functional connectivity), and task-evoked functional MRI (i.e., left or right hand motor task activation)-and a multimodal prediction pipeline demonstrated significant predictive power for strength ( = 0.108-0.536, ≤ 0.001), after correcting for sex, the predictive power was substantially reduced ( = -0.038-0.075). Next, we flipped the analysis and demonstrated that each MRI modality and a multimodal prediction pipeline could significantly predict sex (accuracy = 68.0%-93.3%, AUC = 0.780-0.982, < 0.001). However, correcting the brain features for strength reduced the accuracy for predicting sex (accuracy = 57.3%-69.3%, AUC = 0.615-0.780). Here we demonstrate the effects of sex-correlated confounds in brain-based predictive models across multiple brain MRI modalities for both regression and classification models. We discuss implications of confounds in predictive modeling and the development of brain-based MRI biomarkers, as well as possible strategies to overcome these barriers.

Rimmerman, Neta et al. Microglia And Their Lag3 Checkpoint Underlie The Antidepressant And Neurogenesis-Enhancing Effects Of Electroconvulsive Stimulation. Mol Psychiatry 27.2 (2022): 1120-1135. Web.Abstract

Despite evidence implicating microglia in the etiology and pathophysiology of major depression, there is paucity of information regarding the contribution of microglia-dependent molecular pathways to antidepressant procedures. In this study, we investigated the role of microglia in a mouse model of depression (chronic unpredictable stress-CUS) and its reversal by electroconvulsive stimulation (ECS), by examining the effects of microglia depletion with the colony stimulating factor-1 antagonist PLX5622. Microglia depletion did not change basal behavioral measures or the responsiveness to CUS, but it completely abrogated the therapeutic effects of ECS on depressive-like behavior and neurogenesis impairment. Treatment with the microglia inhibitor minocycline concurrently with ECS also diminished the antidepressant and pro-neurogenesis effects of ECS. Hippocampal RNA-Seq analysis revealed that ECS significantly increased the expression of genes related to neurogenesis and dopamine signaling, while reducing the expression of several immune checkpoint genes, particularly lymphocyte-activating gene-3 (Lag3), which was the only microglial transcript significantly altered by ECS. None of these molecular changes occurred in microglia-depleted mice. Immunohistochemical analyses showed that ECS reversed the CUS-induced changes in microglial morphology and elevation in microglial LAG3 receptor expression. Consistently, either acute or chronic systemic administration of a LAG3 monoclonal antibody, which readily penetrated into the brain parenchyma and was found to serve as a direct checkpoint blocker in BV2 microglia cultures, rapidly rescued the CUS-induced microglial alterations, depressive-like symptoms, and neurogenesis impairment. These findings suggest that brain microglial LAG3 represents a promising target for novel antidepressant therapeutics.

Mackey, Sean et al. Mindfulness-Based Stress Reduction, Cognitive Behavioral Therapy, And Acupuncture In Chronic Low Back Pain: Protocol For Two Linked Randomized Controlled Trials. Jmir Res Protoc 11.9 (2022): e37823. Web.Abstract

BACKGROUND: Nonpharmacologic mind-body therapies have demonstrated efficacy in low back pain. However, the mechanisms underlying these therapies remain to be fully elucidated.

OBJECTIVE: In response to these knowledge gaps, the Stanford Center for Low Back Pain-a collaborative, National Institutes of Health P01-funded, multidisciplinary research center-was established to investigate the common and distinct biobehavioral mechanisms of three mind-body therapies for chronic low back pain: cognitive behavioral therapy (CBT) that is used to treat pain, mindfulness-based stress reduction (MBSR), and electroacupuncture. Here, we describe the design and implementation of the center structure and the associated randomized controlled trials for characterizing the mechanisms of chronic low back pain treatments.

METHODS: The multidisciplinary center is running two randomized controlled trials that share common resources for recruitment, enrollment, study execution, and data acquisition. We expect to recruit over 300 chronic low back pain participants across two projects and across different treatment arms within each project. The first project will examine pain-CBT compared with MBSR and a wait-list control group. The second project will examine real versus sham electroacupuncture. We will use behavioral, psychophysical, physical measure, and neuroimaging techniques to characterize the central pain modulatory and emotion regulatory systems in chronic low back pain at baseline and longitudinally. We will characterize how these interventions impact these systems, characterize the longitudinal treatment effects, and identify predictors of treatment efficacy.

RESULTS: Participant recruitment began on March 17, 2015, and will end in March 2023. Recruitment was halted in March 2020 due to COVID-19 and resumed in December 2021.

CONCLUSIONS: This center uses a comprehensive approach to study chronic low back pain. Findings are expected to significantly advance our understanding in (1) the baseline and longitudinal mechanisms of chronic low back pain, (2) the common and distinctive mechanisms of three mind-body therapies, and (3) predictors of treatment response, thereby informing future delivery of nonpharmacologic chronic low back pain treatments.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02503475; https://clinicaltrials.gov/ct2/show/NCT02503475.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/37823.

Dinur, Eyal et al. A Novel Anti-Inflammatory Formulation Comprising Celecoxib And Cannabidiol Exerts Antidepressant And Anxiolytic Effects. Cannabis Cannabinoid Res (2022). Web.Abstract

Ample research shows that anti-inflammatory drugs, particularly celecoxib, exert antidepressant effects, especially in patients with microglia activation. However, substantial cardiovascular adverse effects limit celecoxib's usefulness. Given that cannabidiol (CBD) exerts anti-inflammatory, microglia-suppressive, and antidepressant effects, we hypothesized that it may potentiate the therapeutic effects of celecoxib. The effects of celecoxib, CBD, and their combination were examined in murine models of antidepressant- and anxiolytic-like behavioral responsiveness, including the forced swim test (FST), elevated plus maze (EPM), lipopolysaccharide (LPS)-induced neuroinflammation, and chronic social defeat stress (CSDS), as well as in microglia cell cultures. Acute administration of a combination of celecoxib plus CBD, at doses that had no effects by themselves (10 and 5 mg/kg, respectively), produced significant antidepressant- and anxiolytic-like effects in the FST and EPM, in male and female mice. In the LPS model, combinations of celecoxib (10 or 20 mg/kg) plus CBD (30 mg/kg) reversed the anxiety-like behavior in the open-field test (OFT) and anhedonia in the sucrose preference test (SPT), with minimal effects of celecoxib or CBD by themselves. In the CSDS paradigm, a combination of celecoxib plus CBD (each at 30 mg/kg) reversed the deficits in the OFT, EPM, social exploration, and SPT, whereas celecoxib or CBD by themselves had partial effects. In BV2 microglia cultures stimulated with LPS or α-synuclein, CBD markedly potentiated the suppressive effects of celecoxib over TNFα (tumor necrosis factor-α) and IL (interleukin)-1β secretion. Combinations of celecoxib plus CBD produce efficacious antidepressant- and anxiolytic-like effects, which may depend on their synergistic microglia-suppressive effects.

Bar-Lev Schleider, Lihi et al. Adherence, Safety, And Effectiveness Of Medical Cannabis And Epidemiological Characteristics Of The Patient Population: A Prospective Study. Front Med (Lausanne) 9 (2022): 827849. Web.Abstract

BACKGROUND: Despite the absence of rigorous prospective studies, there has been an increase in the use of cannabis-based medicinal products. During the study period, the use of medical cannabis in Israel was tightly regulated by national policy. Through a prospective study of approximately 10,000 patients, we aimed to characterize the medical cannabis patient population as well as to identify treatment adherence, safety, and effectiveness.

METHODS AND FINDINGS: In this study of prescribed medical cannabis patients, adherence, safety, and effectiveness were assessed at 6 months. Treatment adherence was assessed by the proportion of patients purchasing the medication out of the total number of patients (excluding deceased cases and patients transferred to another cannabis clinic). Safety was assessed by the frequency of the side-effects, while effectiveness was defined as at least moderate improvement in the patient condition without treatment cessation or serious side-effects. The most frequent primary indications requiring therapy were cancer (49.1%), followed by non-specific pain (29.3%). The average age was 54.6 ± 20.9 years, 51.1% males; 30.2% of the patients reported prior experience with cannabis. During the study follow-up, 1,938 patients died (19.4%) and 1,735 stopped treatment (17.3%). Common side-effects, reported by 1,675 patients (34.2%), were: dizziness (8.2%), dry mouth (6.7%), increased appetite (4.7%), sleepiness (4.4%), and psychoactive effect (4.3%). Overall, 70.6% patients had treatment success at 6 months. Multivariable logistic regression analysis revealed that the following factors were associated with treatment success: cigarette smoking, prior experience with cannabis, active driving, working, and a young age. The main limitation of this study was the lack of data on safety and effectiveness of the treatment for patients who refused to undergo medical assessment even at baseline or died within the first 6 months.

CONCLUSIONS: We observed that supervised medical-cannabis treatment is associated with high adherence, improvement in quality of life, and a decrease in pain level with a low incidence of serious adverse events.