bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Cannabinoid Receptor Agonists on the Antinociceptive Effects of Oxycodone in Squirrel Monkeys
Authors: Withey Sarah Louise , Bergman Jack 
Published: November 2023

Opioids remain the most commonly prescribed drug class for the management of moderate to severe pain and, often, high doses that have unwanted behavioral effects are required for effective analgesia. One strategy that has been proposed to avoid prescribing high doses of opioids is co‐administration of a cannabinoid such as Δ9‐tetrahydrocannabinol (THC) that, by providing its own analgesic effects, will reduce opioid dosage. Studies using the warm water tail withdrawal assay, which remains the most commonly used method for assessing antinociception across species, have provided encouraging data in support of this approach. Here, we further study the potential clinical advantage of this approach by determining how different cannabinoid agonists modify the effects of oxycodone on tail withdrawal latency and food‐maintained behavior (reinforcement density, response rate) in squirrel monkeys. Daily sessions were comprised of four 5‐min response components, each preceded by a long timeout during which cumulative doses of drugs (10‐min for oxycodone and 30‐min for THC or the nabilone derivative AM 7444) could be administered. During each component, the completion of a 10‐response fixed‐ratio in the presence of stimulus lights initiated food delivery and a 30‐sec short timeout during which stimulus lights were off and tail withdrawal latency was measured.Results show that all three drugs produced dose related decreases on both measures of food‐maintained behavior but only oxycodone (0.032–0.56 mg/kg) and AM 7444 (0.0032–0.032 mg/kg) produced dose dependent increases in tail withdrawal latency. These antinociceptive effects were produced by doses of both drugs that did not greatly reduce reinforcement density and were more pronounced for oxycodone than the cannabinoid. Pretreatment with the highest dose of THC that did not eliminate responding (0.32 mg/kg) shifted the dose‐effect function for oxycodone's antinociceptive effects upward and leftward and its effects on food‐maintained behavior downward and leftward. Pretreatment with 0.0032 or 0.0056 mg/kg of AM7444 did not appreciably alter the antinociceptive effects of oxycodone whereas pretreatment with the higher dose (0.0056 mg/kg) markedly accentuated the effects of oxycodone on food‐maintained behavior.These data support previous findings that cannabinoid pretreatment can heighten the antinociceptive effects of morphine‐like opioids but indicate also that cannabinoid pretreatment may exacerbate their behaviorally disruptive effects. Thus, this approach to pain management, while effective, may not be appropriate for all therapeutic settings.
Anti‐Nociceptive Effect of Chrysin in Partial Sciatic Nerve Ligation Model
Authors: Sujatha Dodoala , Begum Nazeef , Prasad KVSRG 
Published: November 2023

Chrysin, a natural polyphenol is acclaimed for its anti‐tumor, anti‐oxidant, anti‐allergic and anti‐inflammatory activities. Few reports were available to support its use against neuropathic pain. The current investigation was designed to study and characterize the anti‐nociceptive effects of chrysin in partial sciatic nerve ligation (PSNL) model induced in male Wistar rats. We used capsaicin‐induced nociception test to verify whether chysin acts via transient receptor potential vanilloid (TRPV1) receptors, as in silico studies in our laboratory has shown good binding affinity of chrysin at the vanilloid binding site of the receptor. All the animal protocols were approved by Institutional Animal Ethical Committee (Regd No.1677/PO/RE/S/2012/CPCSEA). The rats received treatment with vehicle (PSNL control), gabapentin (Standard, 25 mg/kg, p.o) or chrysin (100 and 150 mg/kg, p.o.) for 28 days. The various behavioral and biochemical parameters were determined at regular time intervals and histopathological parameters were evaluated at the end of the study. The data was presented as mean ± SEM and one‐factor ANOVA followed by post hoc analysis using Bonferroni test. Chronic treatment with chrysin (100 and 150 mg/kg) significantly and dose‐dependently improved (p < 0.05) the nociceptive threshold, measured as allodynia, thermal hyperalgesia and mechanical hyperalgesia using standard protocols. The decreased activity of superoxide dismutase, catalase, reduced glutathione, membrane bound inorganic phosphate (Na+/K+ Atpases) and increased lipid peroxidation and Ca2+ Atpases were significantly (p < 0.05) restored by chrysin treatment. Histological aberrations induced after PSNL in sciatic nerve were restored by treatment with chrysin (100 and 150 mg/kg, p.o). Intraplantar injection of capsaicin induced flinching and licking response serves as an index of nociception and was observed in all the treated groups. Chrysin treated groups shown marked reduction in both flinching and licking responses when compared to the control group. The biochemical, behavioural and morphological studies clearly revealed that chrysin protects against PSNL induced neuropathic pain in a dose‐response manner which can be attributed to its multiple mode of action on neuropathic pain targets.Support or Funding InformationThe work was funded by Sri Padmavati Mahila Visvavidyalayam under the support given for the post graduate research work.
Effect of Acute and Chronic Stress on Somatic Pain Sensitivity under Circumstances of Indomethacin‐Induced Gastrointestinal Injury in Conscious Rats
Authors: Filaretova Ludmila , Bagaeva Taniana , Iarushkina Natalia 
Published: November 2023

Nonsteroidal anti‐inflammatory drugs (NSAIDs) such as indomethacin (IM) are commonly used; however their use is complicated by the side effects on the gastrointestinal tract. Gastrointestinal injury triggers the changes in visceral as well as somatic pain sensitivity in rats. Here we studied the effect of acute and chronic stress on somatic pain sensitivity under circumstances of IM‐induced gastric injury in conscious rats. Gastric erosion was caused by a single IM injection (35 mg/kg, sc) in preliminary (24 h) fasted rats. Somatic pain sensitivity was assessed by tail flick test. The animals were habituated for tail flick test for 7 days and examined for baseline tail flick latency on day 8. Then, animals were exposed to IM administration with acute or chronic stress or without stress. Cold‐restraint stress at 10 °C for 30 min and keeping at room temperature 1h before IM was used as acute stress. For chronic stress the rats were subjected to unpredictable stress of various modalities for 14 days daily and injected by IM on day 15. Tail flick latencies were measured after stress (before IM) and 4 h after IM administration. Gastric mucosa injury, plasma corticosterone levels, blood pressure, heart rate, adrenal and thymus weight were also measured. IM caused gastric injury 4h after its administration. Acute or chronic stress by itself did not influence gastric mucosa, but its action manifested under circumstances of IM‐induced gastric injury. Acute stress attenuated the ulcerogenic effect of IM on gastric mucosa, but chronic stress potentiated it. The formation of gastric erosion was accompanied by an increase in tail flick latencies (somatic hypoalgesia). We did not observe any changes in tail flick latencies 1h after cold‐restaint stress. However, acute stress prevented somatic hypoalgesia induced by gastric injury. In contrast to acute stress, chronic stress attenuated tail flick latencies before IM administration, but did not affect somatic hypoalgesia. The data obtained suggests that chronic stress aggravates the ulcerogenic action of IM on gastric mucosa that is accompanied by an increase in somatic pain sensitivity, whereas acute stress plays the protective role in the maintenance of integrity of gastric mucosa and preventing of pain abnormalities induced by pathological process in stomach.Support or Funding InformationThe study was supported by grant of Russian Science Foundation (RSF) №14‐15‐00790.
ARHGEF10 Knockout Mice Exhibit Autism‐Like Behavior and Altered Pain Sensation
Authors: Lu DaiHua , Liou Houng‐Chi , Liao Hsiao‐Mei , Chen Chia‐Hsiang , Gau Susan Shur‐Fen , Fu Wen‐Mei 
Published: November 2023

Autism spectrum disorder (ASD) is a complex neurodevelopment disorder which can cause social, communication and development problems. Genetics certainly play a crucial role in ASD, however, how these different genes affect autistic‐like behavior is still unknown. Our previous CNV study discovered several novel CNVs associated ASD. Among the deleted CNV regions, a missense mutation of the ARHGEF10 is found to be the contributory factor in central nervous system diseases. Here we identified a new autism‐related gene, ARHGEF10, that codes a Rho guanine exchange factor 10 which is a member of guanine nucleotide exchange factor (GEF) family and activates small GTPases but preferentially for RhoA. To follow these CNV findings and gain deep insight into the pathogenesis of autism, we generated a ARHGEF10 knockout mice based on the identification of the patient with 8p23 terminal deletion.We found that the mice lacking ARHGEF10 displayed hyper‐locomotor activity in open field and alternated anxiety behavior in plus maze test. In addition, ARHGEF10 knockout mice showed impaired social interaction and social recognition in three‐chamber test. Moreover, the response to plantar and formalin test was reduced in ARHGEF10 knockout mice. However, knockout ARHGEF10 did not affect spatial learning memory and sensory motor gating.Our findings demonstrate that ARHGEF10 knockout mice displayed key symptoms of autism spectrum condition in human including decreased social interaction and increase spontaneous activities, reduced pain sensation. These results, together with the finding of CNVs in ASD patient, demonstrated that ARHGEF10 may be a candidate gene of autism.Support or Funding InformationThis work was supported by the Ministry of Science and Technology grants, 105‐2321‐B‐002‐020, Taiwan.
&[Beta]ETA‐CYCLODEXTRIN‐COMPLEXED WITH LIPPIA GRATA LEAVES ESSENTIAL OIL REDUCES HYPERALGESIA IN MICE
Authors: Quintans Jullyana Siqueira , Siqueira‐Lima Pollyana , Menezes Erik Pereira , Filho Heitor Gomes Araújo , Araujo Adriano , Rezende Marilia M , Amarante Ruthy Kellen Lima , de Souza Barreto Rosana , Lucchese Angelica , Quintans Lucindo José 
Published: November 2023

Lippia grata Schauer is a medicinal plant native of the semi‐arid area of Northeastern Brazil used in folk medicine as analgesic, anti‐inflammatory and antispasmodic. The leaf essential oil (EO) obtained from L. grata is rich in camphor, (E)‐caryophyllene, bicyclogemacrene, camphene and borneol which has already demonstrated analgesic profile. The pharmacological uses of EO could be limited by short half‐life and insolubility in water but β‐cyclodextrin (CD) could be an effective tool to improve this. Thus, we assessed the pharmacological profile of EO and EO complexed with CD (CDEO) in a model of neuropathic pain induced by injury of the sciatic nerve and in an inflammatory model (pleurisy model) in mice. All experiments were approved by the Animal and Use Committee of the Federal University of Sergipe (CEPA/UFS# 65/2015). Mice were pretreated with EO and CDEO (24 mg/kg, orally route) or vehicle at 7 days after surgery and 1h before carrageenan pleural injection. The treatment with EO and CDEO were able to promote antihyperalgesic effect in mechanical (analgesymeter) and increase latency for thermal stimulation (hot plate test) (p< 0,001) when compared with control group. The treatment with EO or CDEO were effective in reducing the leukocyte influx to pleural cavity and also reduced levels (p < 0,001) of IL‐1beta and TNF‐alpha in the pleural lavage. Moreover, no motor abnormalities were observed after treatment with EO and CDEO. Our findings demonstrated that EO and CDEO possess an analgesic and anti‐inflammatory profile in neuropathic pain and inflammatory models respectively, which seems to be involved by reduction of pro‐inflammatory cytokines.Support or Funding InformationCNPq, CAPES, FAPITEC‐SE, FINEP
Differing Roles of S1P Receptor Adaptation in FTY720‐Induced Antinociception in Acute Versus Neuropathic Pain
Authors: Selley Dana E. , Wilkerson Jenny L. , Welch Sandra P. , Donvito Giulia , Lichtman Aron H. , Sim‐Selley Laura J. 
Published: November 2023

Chronic neuropathic pain is difficult to treat because currently available medications have limited effectiveness and/or serious side effects, including abuse liability. Therefore, new approaches are needed to treat this condition. The immunomodulatory pro‐drug FTY720, which when phosphorylated acts as an agonist for G‐protein‐coupled S1P receptors (S1PR) including S1PR1, 3, 4 an 5, has been shown to be antinociceptive in rodent models of neuropathic pain. S1P and S1PR agonists also produce antinociception in acute thermal pain models in rodents. Here we show that FTY720 produces both acute thermal antinociception and alleviation of allodynia in the chronic constriction injury (CCI) model of neuropathic pain in mice. These effects were both dose‐dependent and mimicked by the S1PR1 selective agonist CYM‐5442. Importantly, repeated administration of FTY720 for one week produced tolerance to the acute thermal antinociceptive effect of the drug, but did not produce tolerance to its anti‐allodynic effect in the CCI model. Examination of S1PR‐stimulated G‐protein activation using agonist‐stimulated [35S]GTPγS autoradiography revealed apparent desensitization of G‐protein activation stimulated by S1P or the S1PR1 agonist SEW2871 throughout the brain. Similar results were seen in membranes prepared from the spinal cord, whereby S1P concentration‐effect curves showed that the Emax value of S1PR‐stimulated [35S]GTPγS binding was greatly reduced in repeated FTY720‐treated mice. These results suggest that S1PR1 is the primary target of FTY720 in alleviation of both acute thermal pain and chronic neuropathic pain induced by nerve injury. Furthermore, the finding that tolerance develops to the antinociceptive effect of FTY720 in acute thermal pain but not in chronic neuropathic pain suggests a differential mechanism of FTY720 action between these two models. Because S1PR1 signaling was desensitized throughout the CNS after repeated FTY720 treatment, it is possible that that this loss in receptor signaling could be responsible for both tolerance to acute thermal antinociception and for the anti‐allodynic action of FTY720 in the CCI model. Therefore, activation of S1PR1 could be responsible for acute thermal antinociception, whereas desensitization of S1PR1 could contribute to the anti‐allodynic effect in neuropathic pain by producing functional antagonism of pro‐nociceptive S1PR1 signaling.Support or Funding InformationSupported by NIH grant R01‐NS093990 from the National Institute of Neurological Disorders and Stroke.
The Transition from Stochastic to Collective Activation of Nicotinic Acetylcholine Receptors Facilitates Information Transmission Within in vitro Hippocampal Networks
Authors: Djemil Sarra , Chen Xin , Dzakpasu Rhonda 
Published: November 2023

Although modulatory in nature, nicotinic acetylcholine receptors (nAChRs) play a major role in the central nervous system, making them one of the most studied receptor class. While both activation and desensitization are phenomena associated with the functions of individual receptors, their effects will clearly manifest on the network/circuit spatial scale. In this study, nicotine was used to investigate the impact of activation and desensitization of nAChRs on cultured hippocampal networks. We assess network dynamics via the recording of extracellular action potentials using a microelectrode array system (MEA). We bath applied either a single dose or two successive doses of increasing concentration of nicotine. We hypothesize that a high concentration of nicotine will facilitate information transmission but pre‐incubation of the network with a low concentration of nicotine would attenuate facilitation. We show that the low concentration has minimal effects on network activity and we call this a network‐desensitized state. A high concentration significantly impacted both spiking and bursting activity and we call this a network‐activated state. Interestingly, a low concentration pre‐incubation of nicotine blocked or significantly diminished activity when followed by a high concentration. Lastly, network synchronization as well as network efficiency increased with the large nicotine concentration. This suggests that although fleeting, the process of global receptor activation has a longer lasting impact on the network than a stochastic receptor activation.Support or Funding InformationNational Science Foundation grant no. PHY‐1205919
Pharmacologic Inhibition and Genetic Elimination of p38α MAPK Normalizes Serotonergic System Alterations and Social Behavior Deficits in the SERT Ala56 Mouse Model of Autism Spectrum Disorder
Authors: Robson Matthew J. , Quinlan Meagan A. , Veenstra‐VanderWeele Jeremy , Watterson D. Martin , Blakely Randy D. 
Published: November 2023

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder exhibiting language and communication deficits, perturbations in social interactions, and rigid, repetitive behaviors. Currently, it is estimated that nearly 1 in 65 children lie on the diagnosable spectrum of ASD. Amplifying this problem, there are no FDA approved medications that alleviate the core symptoms of the disorder. Genetic variation in the SLC6A4 gene that encodes the serotonin (5‐HT) transporter (SERT) has been associated with both ASD and hyperserotonemia, a well‐replicated ASD biomarker. Mice that express the ASD‐associated SERT coding variant Ala56 exhibit hyperserotonemia, elevated CNS 5‐HT clearance, a hypersensitivity of 5‐HT1A and 5‐HT2A receptors and multiple ASD‐like behavioral phenotypes including alterations in social interactions. SERT protein in Ala56 mice exhibit hyperphosphorylation which can be normalized by inhibition of p38 MAPK. Of the four known isoforms of p38 MAPK (α, β, γ, and δ), work has revealed p38α MAPK as the primary isoform responsible for SERT regulation. We hypothesized that selective, CNS penetrant, p38α MAPK inhibitors such as the recently developed MW108 or MW150 might attenuate one or more ASD‐like phenotypes in the SERT Ala56 model. Treatment with MW108 (10mg/kg, QD × 1 week) or MW150 (5 mg/kg, QD × 1 week) normalized SERT Ala56‐mediated hypersensitivity of 5‐HT1A and 5‐HT2A receptors. Further chronic treatment with MW150 normalized SERT Ala56‐mediated increases in hippocampal 5‐HT clearance. Chronic MW108 or MW150 treatment normalized SERT Ala56‐mediated social deficits in the tube test without concomitant changes in midbrain SERT protein levels or changes in tissue levels of monoamine neurotransmitters or their metabolites. Acute MW150 (5 mg/kg) treatment lacked effect on 5‐HT receptor and social behavioral indices. Moreover, genetic elimination of p38α MAPK in 5‐HT neurons of SERT Ala56 mice resulted in the normalization of 5‐HT2A receptor hypersensitivity and social deficits in the tube test as compared to their SERT Ala56 counterparts. Our findings support the conclusion that ongoing p38α MAPK signaling sustains the hyperfunction of SERT Ala56 and subsequent alterations in 5‐HT signaling and behavior. These are the first studies to provide pharmacologic and genetic evidence that targeting p38α MAPK signaling may be a potential therapeutic path for the treatment of ASD.Support or Funding InformationThis work was supported by NIH grants MH078028, MH094527, NS007491 and U01AG043415. Additional support was provided by the Simons Foundation Autism Research Initiative, the PhRMA Foundation and the Brain & Behavior Research Foundation.
Expression and functional characterization of PEA‐15 within the suprachiasmatic nucleus
Authors: Wheaton Kelin , Queiroz Lucas Sales , Sullivan Kyle , Obrietan Karl , Hoyt Kari 
Published: November 2023

The circadian (24 hour) timing system regulates the functional features of most, if not all, physiological process. As such, disruption of the circadian timing system has been shown to have profound negative effects on health, cognition, and to contribute to an array of disease states. Central to the mammalian circadian timing system is the suprachiasmatic nucleus (SCN) of the hypothalamus. This brain structure (often referred to as the ‘master clock’) generates timing cues that coordinates the phasing and amplitude of oscillator populations found throughout the brain, and in peripheral organ systems, such as the liver, lungs and heart. Notably, phasing of the SCN is tightly regulated by photic input signals that are relayed from the retina. The p44/42 mitogen‐activated protein kinase (MAPK) pathway has been shown to be a critical component of the SCN timing system and to function as a key route through which the photic input resets the clock. Here, we investigated cellular mechanisms that regulate ERK (the key effector kinase of the MAPK pathway) phosphorylation and its cellular localization within the SCN. To this end, we examined the expression and function of phosphoprotein enhanced in astrocytes (PEA‐15), a scaffold protein that has been shown to regulate both the activation state of ERK and its subcellular localization. A combination of immunohistochemical labeling and Western analysis methods revealed that PEA‐15 is highly expressed within the mouse SCN. Furthermore, expression profiling detected a significant circadian oscillation in PEA‐15 within the SCN; interestingly, the peak in PEA‐15 expression was antiphase to the well‐characterized circadian oscillation in ERK activity. Photic stimulation of mice led to a significant increase in PEA‐15 phosphorylation at serine‐104, an event that is responsible for the dissociation of ERK from PEA‐15. Consistent with this, co‐immunoprecipitation of ERK and PEA‐15 from SCN lysates revealed that PEA‐15 is directly bound to ERK, and that photic stimulation triggers the dissociation of ERK from PEA‐15. Together, these data reveal that, 1) PEA‐15 is expressed in the SCN, 2) PEA‐15 expression is under the control of the circadian timing system, and 3) PEA‐15 regulates signaling via the MAPK pathway. Given that MAPK signaling is a key regulator of the clock timing system, the data reported here raise the prospect that PEA‐15 could play a key role in modulating the functionality of the SCN timing system. Ongoing work is focused on an examination of potential mechanism by which PEA‐15 affects the timing properties of the SCN.Support or Funding InformationThis work was supported by NIH MH103361.