Withdrawal Response Research Articles

Strain Localization at Volcanoes Undergoing Extension: Investigation of Long‐Term Deformation at Krafla and Askja Volcanic Systems in North Iceland

AbstractVolcanoes in extensional environments may show gradual subsidence over decades during quiescent periods, due to various processes such as magma withdrawal, cooling, contraction, plate spreading and viscoelastic response. If significant rheological anomalies reside in volcano roots, due to the presence of magma and hot rock, they can influence the style of deformation. We use Finite Element Method (FEM) models to explore how strain localization due to extension can lead to volcano deflation. We apply rheological models comprising an elastic layer overlying a viscoelastic domain and include local up‐doming regions of low viscosity material beneath volcanic centers. The models reveal a localized subsidence above the rheological anomaly, influenced by the tectonic extension, and by the up‐doming volume and its viscosity. The models suggest that plate divergence may account for 4–5 mm/yr of observed subsidence at Krafla and Askja volcanic systems (KVS and AVS, respectively) in North Iceland.

Time after time: The influence of perceived coworker overtime, affect and workaholism on daily withdrawal responses

Time after time: The influence of perceived coworker overtime, affect and workaholism on daily withdrawal responses

Xylazine’s Impacts on the Community in Philadelphia: Perspectives of People Who Use Opioids and Harm Reduction Workers

Background Xylazine is in 99% of the fentanyl supply in Philadelphia, PA and is on the rise throughout the United States. Perspectives about this emerging crisis among people who use opioids (PWUO) and harm reduction workers are lacking. Methods We conducted focus groups with PWUO and harm reduction workers in Philadelphia, PA. Discussions focused on xylazine’s impact on PWUO. Transcripts were coded for thematic analysis. Results Themes across focus groups included xylazine withdrawal, wounds, safety concerns, and overdose response implications. Participants emphasized extreme xylazine withdrawal and the difficulty of withdrawal management. Groups explored potential roles of first responders in addressing xylazine-related wounds. PWUO were receptive to receiving help, but many harm reduction workers expressed reservations about partnering with police. Discussion Results underscore the impact of xylazine withdrawal on PWUO. Emerging information on withdrawal management should be shared among care providers to identify optimal protocols. Safety-planning with PWUO should be explored, but structural interventions are imperative. While there may be a role for first responders in delivering harm reduction interventions, it is important to recognize historical harms by first responders against PWUO.

YTHDF1 in periaqueductal gray inhibitory neurons contributes to morphine withdrawal responses in mice

BackgroundPhysical symptoms and aversion induced by opioid withdrawal strongly affect the management of opioid addiction. YTH N6-methyladenosine (m6A) RNA binding protein 1 (YTHDF1), an m6A-binding protein, from the periaqueductal gray (PAG) reportedly contributes to morphine tolerance and hyperalgesia. However, the role of YTHDF1 in morphine withdrawal remains unclear.MethodsA naloxone-precipitated morphine withdrawal model was established in C57/BL6 mice or transgenic mice. YTHDF1 was knocked down via adeno-associated virus transfection. Combined with the results of the single-cell RNA sequencing analysis, the changes in morphine withdrawal somatic signs and conditioned place aversion (CPA) scores were compared when YTHDF1 originating from different neurons in the ventrolateral periaqueductal gray (vlPAG) was knocked down. We further explored the role of inflammatory factors and transcription factors related to inflammatory response in morphine withdrawal.ResultsOur results revealed that YTHDF1 expression was upregulated in the vlPAG of mice with morphine withdrawal and that the knockdown of vlPAG YTHDF1 attenuated morphine withdrawal-related somatic signs and aversion. The levels of NF-κB and p-NF-κB were reduced after the inhibition of YTHDF1 in the vlPAG. YTHDF1 from vlPAG inhibitory neurons, rather than excitatory neurons, facilitated morphine withdrawal responses. The inhibition of YTHDF1 in vlPAG somatostatin (Sst)-expressing neurons relieved somatic signs of morphine withdrawal and aversion, whereas the knockdown of YTHDF1 in cholecystokinin (Cck)-expressing or parvalbumin (PV)-expressing neurons did not change morphine withdrawal-induced responses. The activity of c-fos + neurons, the intensity of the calcium signal, the density of dendritic spines, and the frequency of mIPSCs in the vlPAG, which were increased in mice with morphine withdrawal, were decreased with the inhibition of YTHDF1 from vlPAG inhibitory neurons or Sst-expressing neurons. Knockdown of NF-κB in Sst-expressing neurons also alleviated morphine withdrawal-induced responses.ConclusionsYTHDF1 originating from Sst-expressing neurons in the vlPAG is crucial for the modulation of morphine withdrawal responses, and the underlying mechanism might be related to the regulation of the expression and phosphorylation of NF-κB.

Nociceptive threshold measurement as a non‐invasive functional test of an epidural injection in a dog

AbstractWe present a case of a 3‐year‐old, male Border Collie with severe hip dysplasia and osteoarthritis undergoing total hip replacement, notably having a history of a previous hip surgery with inadequate epidural analgesia. Our objective was to evaluate epidural efficacy before surgery using nociceptive threshold measurement. Nociceptive thresholds were measured with transdermal electrical stimulation via the Dolosys Pain Tracker device. The dog received epidural ropivacaine and morphine, resulting in a cessation of withdrawal response and electromyographic activity. This effect was confirmed under anaesthesia. Postoperatively, the dog recovered without relevant complications. In conclusion, nociceptive threshold measurement using the Dolosys Pain Tracker device allowed immediate confirmation of epidural efficacy, reducing the risk of intraoperative analgesic inadequacy. This approach may enhance surgical pain management in challenging cases.

Evaluation of Anti-arthritic and in-vitro Anti-inflammatory activity of Vaisvanara Churna

Ethnopharmacological relevanceVaisvanara Churna used traditionally for the treatment of Amavata (Rheumatoid arthritis), Shotaprasamana (Anti-inflammatory) and as Saraka (Laxative). AimAim of the study is to evaluate anti arthritic activity and in vitro anti-inflammatory potential of Vaisvanara Churna in experimental animals. Materials and methodsIn-vitro anti-inflammatory activity of aqueous extract of Vaisvanara Churna (100–500 μg/ml) was evaluated by using membrane stabilization methods. Anti arthritic activity was evaluated by using 0.1 ml of Complete Freund's Adjuvant (CFA) injected into sub plantar surface of left hind paw of each wistar rat on day 1 followed by treatment with Vaisvanara Churna at various dose levels (450, 900, and 1800 mg/kg b.w) and standard drug Prednisolone (5 mg/kg) for 21 days. The following parameters namely change in the body weight of animals, paw volume, ankle joint thickness were measured at 0, 3, 8, 17 & 21 day intervals and radiographic changes were assessed. In addition to this, response to painful stimuli by application of forced pressure was measured by using Pressure Application Measurement (PAM) method. ResultsIn-vitro anti-inflammatory activity Vaisvanara Churna exhibited dose dependent membrane stabilizing activity. Treatment with Vaisvanara Churna showed significant (p < 0.05) inhibition of paw edema, reduction in ankle joint thickness and increase in the body weight of wistar albino rats was observed. There is a significant increase (p < 0.001) in the latency of limb withdrawal response, reduction in the organ indices (spleen and thymus) were noted. ConclusionThis study demonstrates that Vaisvanara Churna possesses in vitro anti inflammatory and anti-arthritic potential and supports its folklore use in the treatment of arthritis.

Using DeepLabCut-Live to probe state dependent neural circuits of behavior with closed-loop optogenetic stimulation.

Closed-loop behavior paradigms enable us to dissect the state-dependent neural circuits underlying behavior in real-time. However, studying context-dependent locomotor perturbations has been challenging due to limitations in molecular tools and techniques for real-time manipulation of spinal cord circuits. We developed a novel closed-loop optogenetic stimulation paradigm that utilizes DeepLabCut-Live pose estimation to manipulate primary sensory afferent activity at specific phases of the locomotor cycle in mice. A compact DeepLabCut model was trained to track hindlimb kinematics in real-time and integrated into the Bonsai visual programming framework. This allowed an LED to be triggered to photo-stimulate sensory neurons expressing channelrhodopsin at user-defined pose-based criteria, such as during the stance or swing phase. Optogenetic activation of nociceptive TRPV1 + sensory neurons during treadmill locomotion reliably evoked paw withdrawal responses. Photoactivation during stance generated a brief withdrawal, while stimulation during swing elicited a prolonged response likely engaging stumbling corrective reflexes. Comparison with Existing Methods: This new method allows for high spatiotemporal precision in manipulating spinal circuits based on the phase of the locomotor cycle. Unlike previous approaches, this closed-loop system can control for the state-dependent nature of sensorimotor responses during locomotion. Integrating DeepLabCut-Live with optogenetics provides a powerful new approach to dissect the context-dependent role of sensory feedback and spinal interneurons in modulating locomotion. This technique opens new avenues for uncovering the neural substrates of state-dependent behaviors and has broad applicability for studies of real-time closed-loop manipulation based on pose estimation. Highlights: Closed-loop system probes state-dependent behaviors at pose-modulated instancesBonsai integrates DeepLabCut models for real-time pose estimation during locomotion Phase-dependent TRPV1 + sensory afferent photostimulation elicits context-specific withdrawal responses.

Electronic von Frey associated with the Mouse Grimace Scale to Assess Allodynia and Pain in Trypanosoma evansi-Infected Mice.

Infectious disease pathogenesis is still a complex field to study. The course of several clinical signs, such as allodynia and pain, may be observed in domestic animals. However, the knowledge of their pathways and correct treatment need controlled experiments, many of them using laboratory animals. Measuring changes in mechanical thresholds of the hind paw and viscera is a useful technique to observe changes in pain perception in rodents. Withdrawal response can be measured first in baseline tests, which creates better control of experimental groups. Subsequent tests can be performed after inducing infection and adding drugs to the protocol. The use of an electronic von Frey apparatus associated with the use of a facial scale to observe pain-like changes allows a simple, precise, and consistent assessment to evaluate allodynia and pain in mice. Thus, experiments using the present methodology for Trypanosoma evansi infection represent a useful method to evaluate allodynia and pain in laboratory-infected animals, which can be applied to the conventional treatment for livestock animals.

S1P/S1PR1 signaling is involved in the development of nociceptive pain.

Pain is a complex perception involving unpleasant somatosensory and emotional experiences. However, the underlying mechanisms that mediate its different components remain unclear. Sphingosine-1-phosphate (S1P), a metabolite of sphingomyelin and a potent lipid mediator, initiates signaling via G protein-coupled receptors (S1PRs) on cell surfaces. It serves as a second messenger in cellular processes such as proliferation and apoptosis. Nevertheless, the neuropharmacology of sphingolipid signaling in pain conditions within the central nervous system remains largely unexplored and controversial. Chronic nociceptive pain models were induced in vivo by intraplantar injection of 20μL complete Freund's adjuvant (CFA) into the left hind paws. We assessed S1P and S1PR1 expression in the spinal cords of CFA model mice. Functional antagonists of S1PR1 or S1PR1-specific siRNA were administered daily following CFA model establishment. Paw withdrawal response frequency (PWF) and paw withdrawal latency (PWL) were measured to evaluate mechanical allodynia and thermal hyperalgesia, respectively. RT-PCR assessed interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels. Western blotting and immunofluorescence were used to analyze glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule (Iba1), STAT3, ERK, and p38 MAPK protein expression. In the chronic nociceptive pain model induced by CFA, S1P and S1PR1 expression levels were significantly elevated, leading to activation of spinal cord glial cells. S1PR1 activation also promoted MMP2-mediated cleavage of mature IL-1β. Additionally, S1PR1 activation upregulated phosphorylation of STAT3, ERK, and p38 MAPK in glial cells, profoundly impacting downstream signaling pathways and contributing to chronic nociceptive pain. The S1P/S1PR1 axis plays a pivotal role in the cellular and molecular mechanisms underlying nociceptive pain. This signaling pathway modulates glial cell activation and the expression of pain-related genes (STAT3, ERK, p38 MAPK) and inflammatory factors in the spinal dorsal horn. These findings underscore the potential of targeting the S1P system for developing novel analgesic therapies.

Impact of Morphine withdrawal on genes related to the TLR2 pathway expressed in the Prefrontal Cortex.

Millions of people suffer from opioid use disorder, because of the ongoing opioid epidemic. The aversive symptoms of withdrawal are a leading factor for drug relapses, yet there are limited therapeutic options to minimize or prevent withdrawal symptoms. The mechanism behind opioid withdrawal is still not fully understood, thus preventing the development of new therapeutics. This study is an extension of our previously proposed mechanism of a toll-like receptor 2 (TLR2) mediated withdrawal response as a result of morphine induced microbial change that occurs during morphine withdrawal. Transcriptome analysis of the pre-frontal cortex indicated that there was increased expression of genes related to TLR2 signaling in morphine withdrawal treated animals compared to placebo controls. Antibiotic treatment further altered TLR2 related genes, recovering some of the morphine induced effect and leading to additional suppression of some genes related to the TLR2 pathway. Morphine withdrawal induced gene expression was attenuated in a whole body TLR2 knockout model. These results provide more support that TLR2 plays an integral role in morphine withdrawal mechanisms and could be a potential therapeutic target to minimize opioid withdrawal associated co-morbidities.

Cyclic behaviour of Glulam, LVL and GLVL shear walls and their base connections

This paper presents an experimental study aimed at characterizing the lateral cyclic behaviour of Glulam (GL), Laminated Veneer Lumber (LVL), and Glued Laminated Veneer Lumber (GLVL) shear walls anchored to the foundation by means of conventional hold downs and angle brackets, which are fastened to the timber walls with annular ring nails. Monotonic and cyclic tests are conducted on these mechanical anchors, with hold down connections tested under tensile loads and angle bracket connections under shear loads. Withdrawal tests on annular ring nails embedded in GL, LVL, and GLVL elements are also conducted, to investigate the withdrawal response of the fasteners. The experimental tests reveal that the lateral behaviour of GL, LVL, and GLVL shear walls is similar to that of Cross-Laminated Timber (CLT) shear walls, primarily governed by the wall base connections and by the wall geometry. Hold down and angle bracket connections exhibited a mechanical behaviour governed by the steel-to-timber joints, to large extent comparable with that of typical hold downs and angle brackets fastened to CLT elements. Generally, higher ductility and lower load carrying capacity were reached by hold downs and angle brackets fastened to GL elements compared to those reached by hold downs and angle brackets fastened to LVL and GLVL elements. All quantities relevant for the seismic design, such as stiffness, load carrying capacity, ductility, and overstrength factors are calculated and discussed through the paper. These quantities are then compared with results from different experimental investigations on hold downs and angle brackets fastened to CLT elements available in the literature. Finally, an analytical model for the calculation of the lateral load carrying capacity of the shear walls is presented and used to verify that the same calculation models used for CLT shear walls can be adopted for GL, LVL, and GLVL shear walls.

BNT12, a novel hybrid peptide of opioid and neurotensin pharmacophores, produces potent central antinociception with limited side effects

The development of multitarget opioid drugs has emerged as an attractive approach for innovative pain management with reduced side effects. In the present study, a novel hybrid peptide BNT12 containing the opioid and neurotensin (NT)-like fragments was synthesized and pharmacologically characterized. In acute radiant heat paw withdrawal test, intracerebroventricular (i.c.v.) administration of BNT12 produced potent antinociception in mice. The central antinociceptive activity of BNT12 was mainly mediated by μ-, δ-opioid receptor, neurotensin receptor type 1 (NTSR1) and 2 (NTSR2), supporting a multifunctional agonism of BNT12 in the functional assays. BNT12 also exhibited significant antinociceptive effects in spared nerve injury (SNI)-neuropathic pain, complete Freund's adjuvant (CFA)-induced inflammatory pain, acetic acid-induced visceral and formalin-induced pain after i.c.v. administration. Furthermore, BNT12 exhibited substantial reduction of acute antinociceptive tolerance, shifted the dose-response curve to the right by only 1.3-fold. It is noteworthy that BNT12 showed insignificant chronic antinociceptive tolerance at the supraspinal level. In addition, BNT12 exhibited reduced or no opioid-like side effects on conditioned place preference (CPP) response, naloxone-precipitated withdrawal response, acute hyperlocomotion, motor coordination, gastrointestinal transit, and cardiovascular responses. The present investigation demonstrated that the novel hybrid peptide BNT12 might serve as a promising analgesic candidate with limited opioid-like side effects.

Racism Experienced by Callum and His Family in Malorie Blackman's Noughts + Crosses'

Racism has been a prevalent issue ever since the concept of race was known to mankind, due to this fact, a lot of kinds of racism emerged in society.This study explained the experiences of Callum and his family through the levels of racism as well as how they responded towards the racism itself in the novel Noughts + Crosses by Malorie Blackman. This study itself is a literary criticism focusing on sociological approaches by employing two theories, one by Camarra Phylis Jones named levels of racism (2000) and the second one is multimotive theory by Richman &amp; Leary (2009). Based on the analysis of this study, the first level of Jones’ theory seems to be the most prominent out of the three which is the institutional racism, the characters in this novel were restricted or has limited access to quite a lot of government infrastructure, silenced voice, as well as small quantity of representative in power. While the personally-mediated racism manifested itself through the suspicion of minorities; especially Callum, lack of respect from the Crosses, devaluation of minorities’ capabilities, scapegoating, and dehumanization through hate crime and police brutality. In internalized racism there is also evidence of whiteness as in Lynette’s case where she believes herself to be black as well as self-devaluation by the characters themselves for example Ryan who used the slur word to his own race. Callum and his family responded with various types of response, such as Jude who is leaning towards being more aggressive after the experience of racism while Callum at least try to regain relational value within the society with relationship-promoting response as well as trying to exclude or withdraw himself from the society with avoidance or withdrawal response.

Evaluation of the efficacy of the valsalva maneuver and fentanyl administration for attenuating etomidate injection pain: A double-blind clinical trial

Objective: Etomidate is mentioned as one of the rapid intravenous anesthetic drugs whose unique characteristics include hemodynamic stability, negligible respiratory depression, and brain protection. The most common complication of etomidate is intravenous pain during injection. The purpose of this study was to compare the effectiveness of the Valsalva maneuver and fentanyl in reducing the pain caused by etomidate injection for anesthesia induction. Methods: This clinical trial was performed on 96 patients at Alzahra hospital, affiliated with the Isfahan University of Medical Sciences, from January to June 2021. Patients were divided into two groups of 48 people: the Valsalvamaneuver group (group 1) and the fentanyl group (group 2). Blood pressure, heart rate (HR), oxygen saturation, and pain of etomidate injection using the withdrawal response score were graded on a four-point scale (no pain=zero, mild pain=1, average pain=2, and severe pain=3). The collected information was entered into SPSS software version 24. Then, the pain score in the two groups was compared using the chi-square test. The significance level in the present study was P&lt;0.05. Results: The mean HR (P=0.07), mean arterial pressure (MAP) (P=0.33), systolic pressure (P=0.90), diastolic pressure (P=0.67), and oxygen saturation level (P=0.27) at different times between the two groups showed no significant difference (P&gt;0.05). However, during the etomidate injection, the HR increased and after the injection, the HR decreased in both groups (P=0.042). The two groups had no significant difference regarding pain frequency. Conclusion: There was no difference in the effect of the Valsalva maneuver and fentanyl on reducing the pain caused by etomidate injection.

A conserved gastropod withdrawal circuit in Biomphalaria glabrata, an intermediate host for schistosomiasis.

Neuronal signals mediated by the biogenic amine serotonin (5-HT) underlie critical survival strategies across the animal kingdom. This investigation examined serotonin-like immunoreactive neurons in the cerebral ganglion of the panpulmonate snail Biomphalaria glabrata, a major intermediate host for the trematode parasite Schistosoma mansoni. Five neurons comprising the cerebral serotonergic F (CeSF) cluster of B. glabrata shared morphological characteristics with neurons that contribute to withdrawal behaviors in numerous heterobranch species. The largest member of this group, designated CeSF-1, projected an axon to the tentacle, a major site of threat detection. Intracellular recordings demonstrated repetitive activity and electrical coupling between the bilateral CeSF-1 cells. In semi-intact preparations, the CeSF-1 cells were not responsive to cutaneous stimuli but did respond to photic stimuli. A large FMRF-NH2-like immunoreactive neuron, termed C2, was also located on the dorsal surface of each cerebral hemiganglion near the origin of the tentacular nerve. C2 and CeSF-1 received coincident bouts of inhibitory synaptic input. Moreover, in the presence of 5-HT they both fired rhythmically and in phase. As the CeSF and C2 cells of Biomphalaria share fundamental properties with neurons that participate in withdrawal responses in Nudipleura and Euopisthobranchia, our observations support the proposal that features of this circuit are conserved in the Panpulmonata.NEW & NOTEWORTHY Neuronal signals mediated by the biogenic amine serotonin underlie critical survival strategies across the animal kingdom. This investigation identified a group of serotonergic cells in the panpulmonate snail Biomphalaria glabrata that appear to be homologous to neurons that mediate withdrawal responses in other gastropod taxa. It is proposed that an ancient withdrawal circuit has been highly conserved in three major gastropod lineages.

Orally Administered N-Oleoyl Alanine Blocks Acute Opioid Withdrawal Induced-Conditioned Place Preference and Attenuates Somatic Withdrawal following Chronic Opioid Exposure in Rats

(1) Background: Intraperitoneal injections of the endogenous N-acyl amino acid N-Oleoyl alanine (OlAla) effectively reduces both the affective and somatic responses produced by opioid withdrawal in preclinical models. To increase the translational appeal of OlAla in clinical drug applications, the current experiments tested whether oral OlAla pretreatment also attenuates opioid withdrawal in rats. (2) Methods: In Experiment 1, to assess its impact on affective withdrawal behavior, OlAla (0, 5, 20 mg/kg) was orally administered during the conditioning phase of an acute naloxone-precipitated morphine withdrawal conditioned place avoidance task. In Experiment 2, to assess its impact on somatic withdrawal behavior, OlAla (5–80 mg/kg) was orally administered prior to naloxone-precipitated withdrawal from chronic heroin exposure. (3) Results: Pretreatment with oral OlAla at the higher (20 mg/kg), but not lower (5 mg/kg) dose, reduced the establishment of an acute morphine withdrawal-induced conditioned place aversion. Instead, the lower dose of oral OlAla (5 mg/kg) reduced heroin withdrawal-induced abdominal contractions and diarrhea, whereas higher doses were without effect. (4) Conclusions: The results suggest a dose-dependent reduction of opioid withdrawal responses by orally administered OlAla, and further highlight the potential utility of this compound for opioid withdrawal in clinical populations.

Abstract 2962: Chemotherapy induced senescence drives peripheral neuropathy

Abstract Chemotherapy is a mainstay of cancer therapy. Unfortunately, while chemotherapy can profoundly impact disease free survival, it is often accompanied with devastating side effects including hair loss, bone loss, cognitive impairment (referred to as "brain fog"), and peripheral neuropathies. While many of these side effects may subside after the completion of chemotherapy, some persist for a lifetime, substantially compromising the quality of life for survivors. Particularly insidious is chemotherapy-induced peripheral neuropathy (CIPN), which can impair a patient's ability to care for themselves. Shockingly, in over 30% of patients, CIPN persists even after the cessation of chemotherapy, subjecting them to a lifetime of numbness and/or pain. Paclitaxel (PTX), a common treatment for breast cancer, induces CIPN in 61-92% of patients depending on the administered dose. Unfortunately, there are currently no preventative or curative measures for CIPN resulting in side effects that persist for months or even years after the cessation of chemotherapy. Considering chemotherapy can trigger cellular senescence, leading to the release of a diverse array of factors collectively known as the senescence-associated secretory phenotype (SASP) that are capable of negatively influencing neighboring cells. To determine if senescence played a role in CIPN we treated with PTX and found that animals displayed reduced axon innervation in the paws and diminished paw withdrawal responses during the von Frey assay, characteristic symptoms of CIPN. To determine if senescent drove PTX-induced CIPN, we utilized the INKATTAC (INK) mouse, a model in which a p16INK4a promoter drives an inducible suicide transgene to eliminate p16+ senescent cells following treatment with AP20187 (AP). Employing the INK mouse, we successfully prevented CIPN by eliminating PTX-induced senescent cells. Furthermore, through bone marrow (BM) transplant studies using BM from INK mice into wildtype recipients, we failed to prevent CIPN. This result establishes that senescent immune cells, do not contribute to CIPN. In an independent approach, we found that senolytic drugs (kill senescent cells), such as dasatinib and quercetin (DQ) or ABT737 (ABT), effectively prevented and reversed CIPN in mice. Additionally, since the p38MAPK pathway has been shown to regulate SASP mRNA stability, we treated with p38 and MK2 inhibitors and found that inhibition prevented CIPN in mice. To address the mechanism behind CIPN we have carried out single cell RNA sequencing (scRNA-seq) to identify the cell population senescing in response to chemotherapy. These analyses will allow us to understand the mechanisms that drive CIPN and may lead to new treatments for patients suffering from CIPN. Citation Format: Taylor Malachowski, Ganesh Kumar Raut, Xianmin Luo, Satarupa Mullick Bagchi, Sheila Stewart. Chemotherapy induced senescence drives peripheral neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2962.

Inhibition of SIRT1 in the nucleus accumbens attenuates heroin addiction-related behavior by decreasing D1 neuronal autophagy.

This study aimed to investigate the effects of SIRT1 modulation on heroin addiction-like behavior and its possible biological mechanisms. Wild-type C57BL/6J and Sirt1loxp/loxp D1-Cre mice were used in this experiment, and Sirt1 loxp/loxp D1-Cre(-) mice were used as a control for conditional knockout mice. Mice were divided into saline control and heroin-dependent groups. Behavioral methods were used to record the withdrawal response, conditioned place preference (CPP) changes, and open field test results. Transmission electron microscopy (TEM) was used to observe the structure of autophagosomes in nucleus accumbens (NAc) neurons. The expression of SIRT1 and autophagy-related proteins and genes, such as LC3Ⅱ, ATG5 , and ATG7 , was detected in the NAc of each mouse group via western blot, real-time quantitative PCR (qPCR) analyzes, and immunofluorescence. The results of this experiment showed that compared with the saline group, mice in the wild-type heroin-dependent group showed marked withdrawal symptoms, with more autophagosomes observed in NAc via TEM. Compared with wild-type and Sirt1loxp/loxp D1-Cre(-) heroin-dependent groups, CPP formation was found to be reduced in the conditional knockout mouse group, with a significant decrease in spontaneous activity. Western blot, qPCR, and immunofluorescence results indicated that the expression of LC3Ⅱ, ATG-5, and ATG-7 was significantly reduced in the NAc of the Sirt1loxp/loxp D1-Cre(+) group. It was still, however, higher than that in the saline control group. These results suggest that inhibition of Sirt1 expression may prevent heroin-induced addiction-related behaviors via reducing D1 neuronal autophagy.

The role of astrocytic γ-aminobutyric acid in the action of inhalational anesthetics

BackgroundInhalational anesthetics target the inhibitory extrasynaptic γ-aminobutyric acid type A (GABAA) receptors. Both neuronal and glial GABA mediate tonic inhibition of the extrasynaptic GABAA receptors. However, the role of glial GABA during inhalational anesthesia remains unclear. This study aimed to evaluate whether astrocytic GABA contributes to the action of different inhalational anesthetics. MethodsGene knockout of monoamine oxidase B (MAOB) was used to reduce astrocytic GABA levels in mice. The hypnotic and immobilizing effects of isoflurane, sevoflurane, and desflurane were assessed by evaluating the loss of righting reflex (LORR) and tail-pinch withdrawal response (LTWR) in MAOB knockout and wild-type mice. Minimum alveolar concentration (MAC) for LORR, time to LORR, MAC for LTWR and time to LTWR of isoflurane, sevoflurane, and desflurane were assessed. ResultsTime to LORR and time to LTWR with isoflurane were significantly longer in MAOB knockout mice than in wild-type mice (P < 0.001 and P = 0.032, respectively). Time to LORR with 0.8 MAC of sevoflurane was significantly longer in MAOB knockout mice than in wild-type mice (P < 0.001), but not with 1.0 MAC of sevoflurane (P=0.217). MAC for LTWR was significantly higher in MAOB knockout mice exposed to sevoflurane (P < 0.001). With desflurane, MAOB knockout mice had a significantly higher MAC for LORR (P = 0.003) and higher MAC for LTWR (P < 0.001) than wild-type mice. ConclusionsMAOB knockout mice showed reduced sensitivity to the hypnotic and immobilizing effects of isoflurane, sevoflurane, and desflurane. Behavioral tests revealed that the hypnotic and immobilizing effects of inhalational anesthetics would be mediated by astrocytic GABA.

Anhedonia in bipolar depression treated with ketamine

AbstractBackgroundBipolar depression is the major cause of morbidity in patients with bipolar disorder. It affects psychosocial functioning and markedly impairs occupational productivity. Anhedonia is one of the most debilitating symptoms of depression contributing to treatment resistance. It correlates with suicidality, low quality of life, social withdrawal, and poor treatment response. Currently, there is no approved treatment specifically targeting anhedonia. Emerging evidence suggests that ketamine possesses anti‐anhedonic properties in individuals with depression.ObjectivesThe aim of this naturalistic open‐label study was to investigate the effect of add‐on ketamine treatment on anhedonia in treatment resistant bipolar depression.MethodsOur main interest was the change in patient‐reported (Snaith‐Hamilton Pleasure Scale) and rater‐based anhedonia measure (Montgomery–Åsberg Depression Rating Scale‐anhedonia subscale). The secondary aim was to analyze the score change in three Inventory of Depressive Symptomatology‐Self Report (IDS‐SR) domains: mood/cognition, anxiety/somatic, and sleep. Patients underwent assessments at several time points, including baseline, after the third, fifth, and seventh ketamine infusions. Additionally, a follow‐up assessment was conducted 1 week following the final ketamine administration.ResultsWe found improvement in anhedonia symptoms according to both patient‐reported and rater‐based measures. The improvement in IDS‐SR domains was most prominent in anxiety/somatic factor and mood/cognition factor, improvement in sleep factor was not observed. No serious adverse events occurred.ConclusionAdd‐on ketamine seems to be a good choice for the treatment of anhedonia in treatment resistant bipolar depression. It also showed a good effect in reducing symptoms of anxiety in this group of patients. Considering unmet needs and the detrimental effect of anhedonia and anxiety, more studies are needed on ketamine treatment in resistant bipolar depression.