Noxious Stimuli Research Articles

Behavioral and pharmacological characterization of planarian nociception.

Pain mostly arises because specialized cells called nociceptors detect harmful or potentially harmful stimuli. In lower animals with less convoluted nervous system, these responses are believed to be purely nociceptive. Amongst invertebrate animal models, planarians are becoming popular in a wide range of pharmacological and behavioral studies beyond the field of regeneration. Recent publications led the way on pain studies by focusing on nociceptive behaviors such as the 'scrunching' gait displayed under various noxious stimuli, as opposed to the 'gliding' gait planarians usually adopt in normal conditions. In this study, we adapted commonly used nociceptive tests to further explore nociception in planarians of the species Girardia dorotocephala. By using behavioral analysis in open fields and place preferences, we managed to set up chemical, thermal and mechanical nociceptive tests. We also adapted RNA interference protocols and explored the effects of knocking down TRPA1 ion channels, one of the main effectors of chemically and thermally-induced nociceptive responses in vertebrates. Consequently, we demonstrated the reliability of the scrunching gait in this planarian species, which they displayed in a dose-dependent manner when exposed to the irritant AITC. We also showed that suppressing the expression of TRPA1 ion channels completely suppressed the scrunching gait, demonstrating the involvement of TRPA1 nociceptors in this nociceptive reaction. Besides, we also explored the effects of two common analgesics that both displayed strong antinociceptive properties. First, morphine reduced the chemically-induced nociceptive scrunching gaits by more than 20% and shifted the of the dose-response curve by approximately 10 μM. Secondly, the NSAID meloxicam drastically reduced chemically-induced scrunching by up to 60% and reduced heat avoidance in place preference tests. Thus, we managed to characterize both behavioral and pharmacological aspects of G. dorotocephala's nociception, further developing the use of planarians as a replacement model in pain studies and more globally the study of invertebrate nociception.

Correlation of C-Reactive Proteins With Chronic Periodontitis. A Prospective Study

Abstract Context: The C-reactive protein (CRP) is an acute-phase reactant protein that is produced in response to various inflammatory and noxious stimuli that include exposure to heat, traumatic conditions, varieties of infectious processes, and conditions of hypoxia. Estimation of CRP levels in serum samples helps in providing important information related to the diagnosis, monitoring, and treatment of inflammatory processes and various associated diseases. Materials and Methods: This prospective longitudinal study was designed to evaluate serum CRPs in subjects who were selected for study participation after fitting into inclusion criteria, which were as follows: a) study participants who were clinically diagnosed with chronic generalized periodontitis along with periodontal pocket depths of ≥5 mm and also radiographic alveolar bone loss; b) subjects within the age range of 35 to 55 years; and c) no smoking habit or use of tobacco in any other form. Results: Patients were assessed for clinical parameters such as gingival index, sulcular bleeding index, mean depth of periodontal pocket, and loss of clinical attachment. Blood was collected at required visits, and CRP was evaluated. Study evaluation periods were baseline (day 0), day 14 (2nd appointment), and day 45 (3rd appointment). Results: Statistically significant reductions in both clinical and serum CRP levels were obtained at subsequent appointments. Conclusion: This study has demonstrated and supported the evidence that serum CRPs act as a biomarker in determining the prognosis of chronic periodontitis patients after nonsurgical periodontal treatment.

Compound 48/80 causes overactive bladder without altering urothelial permeability in mice

The urothelium, a transitional epithelium lining the urinary bladder, is essential for preventing leakage of urine into the underlying tissue. Disruption of this barrier by noxious stimuli or inflammatory mediators increases bladder wall permeability and causes bladder dysfunction. Compound 48/80 is a pro-inflammatory basic secretagogue that causes urothelium-dependent increases in urinary bladder contractility, as well as bladder overactivity in mice. We hypothesized that Compound 48/80 causes bladder dysfunction by increasing urothelial permeability. Intact bladders from male C57BL/6 mice (N=4) were cannulated, filled with HEPES-buffered physiological salt solution containing FITC-labeled-dextran (70 kDa), and pressurized to 25 mmHg. Z-stacks of baseline fluorescence were captured across the bladder wall using 2-photon laser microscopy. Compound 48/80 (50 μg/mL) was then instilled intravesically for 10 minutes before the bladder wall was imaged again. Average FITC intensity plots wall showed no consistent increase in fluorescence with or without Compound 48/80 from the lumen into the bladder wall. There was also no statistical difference in the area under the curve of these line graphs (p=0.5898). Our findings suggest that Compound 48/80 causes overactive bladder without affecting urothelial permeability. Future studies will investigate other secretagogues and lower molecular weight dextrans to clarify the mechanisms by which secretagogues cause a loss of urothelial barrier function. This research is supported by NIH P20-DK127554 (NRT), NIH R01-DK119615 (NRT). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Quantitative Analysis of CGRP-IR Afferent Axons in the Mouse Stomach Using Zeiss Arivis Vision4D for Automated Tracing

Gastric nociceptive afferents detect and respond to noxious stimuli by transmitting signals from the stomach to the brain. Calcitonin gene-related peptide (CGRP) is a marker for nociceptive afferents and is crucial to gastric functions, including gastric acid secretion, gut motility, and inflammation. However, the topographical quantitative analysis of CGRP-immunoreactive (CGRP-IR) axons in the whole stomach is challenging due to the large amount of axon innervation in various targets within the tissue. Manual tracing of axons is time-consuming, labor-intensive, and extremely tedious, while currently existing automatic neuron tracing programs often need help with large file sizes or tracing inaccuracies. In this study, we used Zeiss Arivis Vision4D, a novel and sophisticated software with a user-guided machine learning capability, for automated tracing of CGRP-IR axons in flat-mounts of the whole mouse stomach muscular layers and thick serial sections of the antrum-pylorus region (C57BL/6J, male, 2-3 months old, n=7). We utilized a combination of techniques, including the Zeiss M2 Imager for automated scanning, Zen 3.3 (blue edition) for image processing, and Vision4D for stitching the entire stomach flat-mounts and sections, 3D fiber tracing, and density analysis. Our results demonstrated that: 1) Vision4D detected and traced almost all CGRP-IR axons of different gastric targets (blood vessels, muscles, myenteric neurons) in different regions (fundus, corpus, antrum) of the stomach. 2) The x-y-z tracing allowed the visualization of axons in space, portraying its continuous trajectory across layers in the muscular flat mounts (longitudinal muscle, myenteric plexus, circular muscle) and cross sections (muscles, submucosa, mucosa). 3) Vision4D also enabled quantitative morphological and laminar analysis based on target and layer separations. The axon density heatmap generated from the tracing data showed high CGRP-IR axon innervation in the blood vessels. After the removal of blood vessels, dense innervation was seen in the upper fundus and antrum-pylorus followed by corpus, indicating the abundance of CGRP in these regions. 4) Vision4D is a powerful tool in handling large data sizes (hundreds of gigabytes of optical sections in more than 300 image frames per stomach) and outstanding in its capability to track nerve fibers in a highly accurate and time effcient manner. This has paved the way for data batch processing to be accessible, as well as shown that multi-marker tracing of the same tissue sample is attainable. 5) The tracing data will be integrated into a stomach scaffold for a 3D map of CGRP-IR afferent axons. This study represents, for the first time, the automatically traced CGRP-IR axons using whole stomach preparations and highlights the potential of Vision4D in creating axon tracing models in other organs and species. This study is supported by NIH 1 U01 NS113867-01, NIH R15 1R15HL137143-01A1 and Carl ZEISS Company. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex Differences in Alpha Synuclein Gastrointestinal Aggregation

Parkinson’s Disease (PD) is a neurodegenerative disorder with prodromal symptoms often emerging decades before motor issues, including gastrointestinal (GI) symptoms such as constipation and visceral pain. The pathological hallmark of PD is accumulation of misfolded α-synuclein (aSyn) protein in the brain and periphery, including the GI tract. Men have two times the risk of developing PD compared to women. However, disease progression and mortality are higher in women, who also report worse GI symptoms. Gut calcitonin gene related peptide (CGRP) is involved in modulating intestinal contractions and pain, and CGRP receptor antagonists lead to constipation. We hypothesize that sex differences in GI symptoms of PD are the result of sex specific aSyn aggregation and differential enteric CGRP signaling. Intraperitoneal injections of the pesticide rotenone were given to C57BL/6J mice to facilitate aggregation of aSyn. Immunohistochemistry was performed on colon sections using antibodies to aSyn, protein gene product (PGP) 9.5, and CGRP. Quantities of aSyn were analyzed in myenteric PGP9.5+ neuronal fibers. Vehicle treated females had 48% (mean +/- SEM = 0.66 μm2 +/- 0.04) less immunoreactive (ir) enteric aSyn than males (1.3 μm2 +/- 0.13; [F(1,22) = 4.8, p < 0.05). Rotenone treatment increased aSyn-ir by 56% (1.5 μm2 +/- 0.13) in females and 28% (1.08 μm2 +/- 0.14) in males. When interrogated by region, rotenone treatment increased the average precent area of CGRP-ir in the apical crypt (male 9% +/- 0.6; female 10% +/- 0.6) compared to vehicle (male 7% +/- 0.8; female 7% +/- 0.7). This increase was 14% higher in females compared to males (F(1,12) = 5.6, p < 0.05). In males and females, the average percent area of CGRP-ir in the mid-basal crypt region decreased with rotenone treatment (male 4% +/- 0.4; female 2.6% +/- 0.1) compared to vehicle (male 3%+/-0.2, female 1.7%+/-0.06; [F(1,12) = 19.62, p < 0.001). Microbiota have been shown to modulate visceral pain via the release of CGRP, and PD patients have altered microbiotas. The larger increase in CGRP-ir at the apical region of crypts after rotenone treatment in females may contribute to sensitivity to noxious stimuli from the lumen, including microbiota and their metabolites. In addition, decreased mid-basal CGRP-ir and aSyn increases in females after rotenone treatment provide valuable data towards explaining increased GI symptoms seen in PD females. Females are significantly understudied within the context of PD, however, investigating the underlying pathophysiology of GI symptoms while addressing sex as a variable could provide clues to the sex differences seen in clinical outcomes. Since these symptoms often arise years before motor dysfunction and diagnosis, it is critical to determine sex specific mechanisms of aSyn aggregation and influence on enteric neural involvement in prodromal GI symptoms. SCORE MGH ORWH U54-MH118919. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Decoding the role of genetically-distinct sensory nerves in controlling cardiopulmonary reflexes

Activation of airway sensory nerves causes respiratory and autonomic reflexes. The majority of the airway sensory afferents are only sensitive to noxious stimuli, such as inflammation, irritants, and pollutants. Activation of these nociceptive afferents evokes protective mechanisms such as apnea, cough, and bradycardia. These reflexes may contribute to disease morbidity when excessively activated. Airway nociceptors, largely projecting from the vagal ganglia (nodose and jugular ganglion), are heterogeneous with respect to gene expression and neuroanatomy, and our objective is to characterize the reflexes evoked by activation of specific afferent subsets using chemogenetics. To selectively activate vagal afferent subpopulations in vivo, mice were exposed to nebulized selective stimuli such as capsaicin (transient receptor potential (TRP) vanilloid 1 (V1) agonist), allyl isothiocyanate (AITC, TRP ankyrin 1 (A1) agonist), and clozapine-N-oxide (CNO, selective agonist for the designer receptor exclusively activated by designer drug (DREADD) stimulatory receptor hM3Dq). hM3Dq expression by ROSA26-loxP-STOP-loxP mice was selectively expressed in sensory subpopulations by breeding with Cre recombinase-expressing mice: TRPV1 (all nociceptors), Tac1-Cre (peptidergic/jugular-originating nerves), and P2X2-Cre (nodose-originating nerves). An intersectional approach using TRPV1-flp mice and the above Cre mice combined with bilateral vagal injections of an AAV delivering dual recombinase-dependent DREADD constructs was used to express hM3Dq in afferent populations defined by two genes (e.g. TRPV1+ and P2X2+). ECGS were recorded via radiotelemetry, and respiration was measured via whole-body plethysmography. CNO administration in TRPV1-hM3Dq mice, P2X2-hM3Dq mice, and Tac1-hM3Dq mice evoked bradypnea and bradycardia. When CNO was administered in the dual recombinase-dependent ConFon (Cre-On/Flp-On) Tac1-Cre/TRPV1-Flp mouse (selectively activating the vagal jugular nociceptors), a significant bradypnea was evoked; however, when CNO was administered in the dual recombinase-dependent ConFon P2X2-Cre/TRPV1-Flp mouse (selectively activating the nodose nociceptors), no bradypnea was observed. Our preliminary data suggest that functionally-distinct nociceptive subpopulations differentially regulate the cardiopulmonary reflexes. NIH R01: 152219, NIH T32: HL160529. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The inflammasome pathway is activated by dengue virus non-structural protein 1 and is protective during dengue virus infection.

Dengue virus (DENV) is a medically important flavivirus causing an estimated 50-100 million dengue cases annually, some of whom progress to severe disease. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis by inducing endothelial barrier dysfunction. However, less is known about how DENV NS1 interacts with immune cells and what role these interactions play. Here we report that DENV NS1 can trigger activation of inflammasomes, a family of cytosolic innate immune sensors that respond to infectious and noxious stimuli, in mouse and human macrophages. DENV NS1 induces the release of IL-1β in a caspase-1 dependent manner. Additionally, we find that DENV NS1-induced inflammasome activation is independent of the NLRP3, Pyrin, and AIM2 inflammasome pathways, but requires CD14. Intriguingly, DENV NS1-induced inflammasome activation does not induce pyroptosis and rapid cell death; instead, macrophages maintain cellular viability while releasing IL-1β. Lastly, we show that caspase-1/11-deficient, but not NLRP3-deficient, mice are more susceptible to lethal DENV infection. Together, these results indicate that the inflammasome pathway acts as a sensor of DENV NS1 and plays a protective role during infection.

Dendrite intercalation between epidermal cells tunes nociceptor sensitivity to mechanical stimuli in Drosophila larvae.

An animal's skin provides a first point of contact with the sensory environment, including noxious cues that elicit protective behavioral responses. Nociceptive somatosensory neurons densely innervate and intimately interact with epidermal cells to receive these cues, however the mechanisms by which epidermal interactions shape processing of noxious inputs is still poorly understood. Here, we identify a role for dendrite intercalation between epidermal cells in tuning sensitivity of Drosophila larvae to noxious mechanical stimuli. In wild-type larvae, dendrites of nociceptive class IV da neurons intercalate between epidermal cells at apodemes, which function as body wall muscle attachment sites, but not at other sites in the epidermis. From a genetic screen we identified miR-14 as a regulator of dendrite positioning in the epidermis: miR-14 is expressed broadly in the epidermis but not in apodemes, and miR-14 inactivation leads to excessive apical dendrite intercalation between epidermal cells. We found that miR-14 regulates expression and distribution of the epidermal Innexins ogre and Inx2 and that these epidermal gap junction proteins restrict epidermal dendrite intercalation. Finally, we found that altering the extent of epidermal dendrite intercalation had corresponding effects on nociception: increasing epidermal intercalation sensitized larvae to noxious mechanical inputs and increased mechanically evoked calcium responses in nociceptive neurons, whereas reducing epidermal dendrite intercalation had the opposite effects. Altogether, these studies identify epidermal dendrite intercalation as a mechanism for mechanical coupling of nociceptive neurons to the epidermis, with nociceptive sensitivity tuned by the extent of intercalation.

Managing established bronchopulmonary dysplasia without using routine blood gas measurements

ObjectiveRoutine blood gas measurements are common in infants with severe bronchopulmonary dysplasia (sBPD) and are a noxious stimulus. We developed a guideline-driven approach to evaluate the care of infants with sBPD without routine blood gas sampling in the chronic phase of NICU care (after diagnosis at 36 weeks PMA).Study designWe examined blood gas utilization and outcomes in our sBPD inpatient care unit using data collected between 2014 and 2020.Results485 sBPD infants met inclusion criteria, and 303 (62%) never had a blood gas obtained after 36 weeks PMA. In infants who had blood gas measurements, the median number of total blood gases per patient was only 4 (IQR 1–10). We did not identify adverse effects on hospital outcomes in patients without routine blood gas measurements.ConclusionsWe found that patients with established BPD could be managed without routine blood gas analyses after 36 weeks PMA.

Anticipating noxious stimulation rather than afferent nociceptive input may evoke pupil asymmetry

Unilateral nociceptive stimulation is associated with subtle signs of pupil asymmetry that may reflect lateralized activity in the locus coeruleus. To explore drivers of this pupil asymmetry, electrical stimuli, delivered alone or 200 ms before or after an acoustic startle stimulus, were administered to one ankle under four experimental conditions: with or without a 1.6 s anticipatory period, or while the forearm ipsilateral or contralateral to the electrical stimulus was heated tonically to induce moderate pain (15 healthy participants in each condition). Pupil diameter was measured at the start of each trial, at stimulus delivery, and each second for 5 s after stimulus delivery. At the start of the first trial, the pupil ipsilateral to the side on which electric shocks were later delivered was larger than the contralateral pupil. Both pupils dilated robustly during the anticipatory period and dilated further during single- and dual-stimulus trials. However, pupil asymmetry persisted throughout the experiment. Tonically-applied forearm heat-pain modulated the pupillary response to phasic electrical stimuli, with a slight trend for dilatation to be greater contralateral to the forearm being heated. Together, these findings suggest that focusing anxiously on the expected site of noxious stimulation was associated with dilatation of the ipsilateral pupil whereas phasic nociceptive stimuli and psychological arousal triggered bilateral pupillary dilatation. It was concluded that preparatory cognitive activity rather than phasic afferent nociceptive input is associated with pupillary signs of lateralized activity in the locus coeruleus.

The Effects of Volatile Anesthetics on Renal Sympathetic and Phrenic Nerve Activity during Acute Intermittent Hypoxia in Rats.

Coordinated activation of sympathetic and respiratory nervous systems is crucial in responses to noxious stimuli such as intermittent hypoxia. Acute intermittent hypoxia (AIH) is a valuable model for studying obstructive sleep apnea (OSA) pathophysiology, and stimulation of breathing during AIH is known to elicit long-term changes in respiratory and sympathetic functions. The aim of this study was to record the renal sympathetic nerve activity (RSNA) and phrenic nerve activity (PNA) during the AIH protocol in rats exposed to monoanesthesia with sevoflurane or isoflurane. Adult male Sprague-Dawley rats (n = 24; weight: 280-360 g) were selected and randomly divided into three groups: two experimental groups (sevoflurane group, n = 6; isoflurane group, n = 6) and a control group (urethane group, n = 12). The AIH protocol was identical in all studied groups and consisted in delivering five 3 min-long hypoxic episodes (fraction of inspired oxygen, FiO2 = 0.09), separated by 3 min recovery intervals at FiO2 = 0.5. Volatile anesthetics, isoflurane and sevoflurane, blunted the RSNA response to AIH in comparison to urethane anesthesia. Additionally, the PNA response to acute intermittent hypoxia was preserved, indicating that the respiratory system might be more robust than the sympathetic system response during exposure to acute intermittent hypoxia.

Neuroendocrine cells initiate protective upper airway reflexes.

Airway neuroendocrine (NE) cells have been proposed to serve as specialized sensory epithelial cells that modulate respiratory behavior by communicating with nearby nerve endings. However, their functional properties and physiological roles in the healthy lung, trachea, and larynx remain largely unknown. In this work, we show that murine NE cells in these compartments have distinct biophysical properties but share sensitivity to two commonly aspirated noxious stimuli, water and acid. Moreover, we found that tracheal and laryngeal NE cells protect the airways by releasing adenosine 5'-triphosphate (ATP) to activate purinoreceptive sensory neurons that initiate swallowing and expiratory reflexes. Our work uncovers the broad molecular and biophysical diversity of NE cells across the airways and reveals mechanisms by which these specialized excitable cells serve as sentinels for activating protective responses.

Low-Efficacy Mu Opioid Agonists as Candidate Analgesics: Effects of Novel C-9 Substituted Phenylmorphans on Pain-Depressed Behavior in Mice.

Low-efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO2 were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ∼1 h. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics. SIGNIFICANCE STATEMENT: This study used a novel set of mu opioid receptor (MOR)-selective opioids with graded MOR efficacies to examine the lower boundary of MOR efficacy sufficient to relieve pain-related behavioral depression in mice. Two novel low-efficacy opioids (JL-2-39, DC-1-76.1) produced effective antinociception with improved safety relative to higher- or lower-efficacy opioids, and results support further consideration of these and other low-efficacy opioids as candidate analgesics.

Comparative Study on the Efficacy of Lignocaine Nebulisation Vs Topical Lignocaine Spray in Attenuation of Haemodynamic Surge in Patients Undergoing Surgery Under General Anaesthesia - A Single Blinded Randomized Controlled Study

Introduction: Laryngoscopy and tracheal intubation are powerful noxious stimuli that should be attenuated. The present study is to compare the efficacy of lignocaine nebulisation vs topical lignocaine spray in attenuation of haemodynamic surge in patients undergoing surgery under general anaesthesia. Methodology: After ethical committee clearance, a single blind randomized control study was done on sixty patients of either sex aged between 18-55 years of ASA status I undergoing elective surgery under general anaesthesia with endotracheal intubation. Patients were randomly allocated into 2 groups: GROUP A:received nebulised Lignocaine Hydrochloride 4% at 2 mg/kg. GROUP B: received Topical Lignocaine spray 10% at 2mg/kg. Heart rate, Systolic, diastolic and mean blood pressure was documented before administering premedication (T0), at the time of intubation (TI) and at 1min (T-1), 2min (T-2) & 5min (T-5) after intubation. Attenuation in HR, SBP, DBP and MBP were found statistically significant (p<0.05) in group A in comparison to group B. Thus in conclusion Lignocaine nebulisation is far more effective in comparison to topical lignocaine spray in attenuation of the laryngoscopic surge. Results: After conducting the study on a total of sixty patients it was found that there was statistically significant reduction in SBP, DBP, MBP and HR in GROUP A receiving lignocaine nebulisation compared to GROUP B receiving topical lignocaine spray. Conclusion: Lignocaine nebulisation is more effective than topical lignocaine spray in attenuation of haemodynamic surge following laryngoscopy and intubation in patients undergoing surgery under general anaesthesia. Keywords: Laryngoscopy, Tracheal Intubation, Lignocaine Nebulisation, Lignocaine Spray, Heamodynamic Surge

Efficacy of Preemptive Analgesia on Pain Perception After Simple Tooth Extraction: A Prospective Study.

Background and objective This study aims to explore the concept of preemptive analgesia, which is the technique of administration of analgesic agents before the painful stimulus. This bridges the time gap between the onset of action of the analgesic agentsand the wear-off of local anesthesia. Existing literature also brings up the concept of central sensitization, which is the hyper-activity of the nervous system in response to a noxious stimulus. Administration of preemptive analgesia prevents central sensitization and hence provides prolonged analgesia to the patient. For the benefit of this study, tab. Etoricoxib 90 mg was used as the analgesic agent. In addition, this study aims to investigate the effects of the administration of tab. Etoricoxib 90 mg 30 minutes before extraction of a single mandibular third molar on the effects of pain experienced by the patient after tooth extraction as compared to a placebo. Methodology This was a double-blinded, prospective, observational study. The pain experienced by 50 participants in each group was measured at 1 hour, 6 hours, 12 hours, and 24 hours postoperatively using a visual analog scale (VAS). The independent samples t-test was then conducted to evaluate the results and draw out conclusions. Results The average difference in pain experienced was maximum in the first hour after the procedure. The mean VAS score reported by patients was 3.14 in the study group but was 6.40 in the control group within the first hour. This difference was reduced in the first six hours after the procedure, with the average score being 3.82 in the study and 7.16 in the control group. The difference was the least after 12 hours, with the study group experiencing a VAS score of 4.64 and controls experiencing a VAS score of 6.14. After the first 24 hours, the mean VAS score was 3.80 in the study group and 5.60 in the control group. Conclusions Preemptive administration of tab. Etoricoxib 90 mg can reduce postextraction pain in healthy adult patients as compared to placebo tablets, with a maximum difference in pain reduction seen at the end of the first six hours (P= 0.012) and the minimum at the end of 12 hours (P= 0.0197).

The Effect of Diesel Exhaust Particles on Adipose Tissue Mitochondrial Function and Inflammatory Status.

Air pollution poses a significant global health risk, with fine particulate matter (PM2.5) such as diesel exhaust particles (DEPs) being of particular concern due to their potential to drive systemic toxicities through bloodstream infiltration. The association between PM2.5 exposure and an increased prevalence of metabolic disorders, including obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM), is evident against a backdrop of rising global obesity and poor metabolic health. This paper examines the role of adipose tissue in mediating the effects of PM2.5 on metabolic health. Adipose tissue, beyond its energy storage function, is responsive to inhaled noxious stimuli, thus disrupting metabolic homeostasis and responding to particulate exposure with pro-inflammatory cytokine release, contributing to systemic inflammation. The purpose of this study was to characterize the metabolic response of adipose tissue in mice exposed to either DEPs or room air (RA), exploring both the adipokine profile and mitochondrial bioenergetics. In addition to a slight change in fat mass and a robust shift in adipocyte hypertrophy in the DEP-exposed animals, we found significant changes in adipose mitochondrial bioenergetics. Furthermore, the DEP-exposed animals had a significantly higher expression of adipose inflammatory markers compared with the adipose from RA-exposed mice. Despite the nearly exclusive focus on dietary factors in an effort to better understand metabolic health, these results highlight the novel role of environmental factors that may contribute to the growing global burden of poor metabolic health.

Immune drivers of physiological and pathological pain.

Physiological pain serves as a warning of exposure to danger and prompts us to withdraw from noxious stimuli to prevent tissue damage. Pain can also alert us of an infection or organ dysfunction and aids in locating such malfunction. However, there are instances where pain is purely pathological, such as unresolved pain following an inflammation or injury to the nervous system, and this can be debilitating and persistent. We now appreciate that immune cells are integral to both physiological and pathological pain, and that pain, in consequence, is not strictly a neuronal phenomenon. Here, we discuss recent findings on how immune cells in the skin, nerve, dorsal root ganglia, and spinal cord interact with somatosensory neurons to mediate pain. We also discuss how both innate and adaptive immune cells, by releasing various ligands and mediators, contribute to the initiation, modulation, persistence, or resolution of various modalities of pain. Finally, we propose that the neuroimmune axis is an attractive target for pain treatment, but the challenges in objectively quantifying pain preclinically, variable sex differences in pain presentation, as well as adverse outcomes associated with immune system modulation, all need to be considered in the development of immunotherapies against pain.

Nerve injury triggers time-dependent activation of the locus coeruleus, influencing spontaneous pain-like behavior in rats.

Dynamic changes in neuronal activity and in noradrenergic locus coeruleus (LC) projections have been proposed during the transition from acute to chronic pain. Thus, we explored the cellular cFos activity of the LC and its projections, in conjunction with spontaneous pain-like behavior in neuropathic rats. Tyrosine hydroxylase:Cre and wild-type Long-Evans rats, males and females, were subjected to chronic constriction injury (CCI) for 2 (short-term, CCI-ST) or 30 days (long-term, CCI-LT), evaluating cFos and Fluoro-Gold expression in the LC, and its projections to the spinal cord (SC) and rostral anterior cingulate cortex (rACC). These tests were carried out under basal conditions (unstimulated) and following noxious mechanical stimulation. LC activity was evaluated through chemogenetic and pharmacological approaches, as were its projections, in association with spontaneous pain-like behaviors. CCI-ST enhanced basal cFos expression in the LC and in its projection to the SC, which increased further after noxious stimulation. Similar basal activation was found in the neurons projecting to the rACC, although this was not modified by stimulation. Strong basal cFos expression was found in CCI-LT, specifically in the projection to the rACC, which was again not modified by stimulation. No cFos expression was found in the CCI-LT LCipsi/contra→SC. Chemogenetics showed that CCI-ST is associated with greater spontaneous pain-like behavior when the LCipsi is blocked, or by selectively blocking the LCipsi→SC projection. Activation of the LCipsi or LCipsi/contra→SC dampened pain-like behavior. Moreover, DREADDs-mediated inactivation of the CCI-ST LCipsi→rACC or CCI-LT LCipsi/contra→rACC pathway, or intra-rACC antagonism of alpha-adrenoreceptors, also dampens pain-like behavior. In the short term, activation of the LC following CCI attenuates spontaneous pain-like behaviors via projections to the SC while increases nociception via projections to the rACC. In the long term, only the projections from the LC to the rACC contribute to modulate pain-like behaviors in this model.

Transmucosal administration of pentobarbital and phenytoin solution induces euthanasia in bearded dragons (Pogona vitticeps).

To assess the efficacy of transmucosal euthanasia solution to induce euthanasia. 6 bearded dragons (Pogona vitticeps). An initial dose of euthanasia solution containing pentobarbital and phenytoin sodium was administered transmucosally in conscious lizards (100 mg/kg pentobarbital dose), followed by a second dose 20 minutes later (400 mg/kg pentobarbital dose). The presence of movement, leakage of euthanasia solution, behaviors consistent with oral irritation, respiratory rate, heart rate, palpebral and corneal reflex, and response to noxious stimuli were recorded until death, confirmed by the absence of Doppler cardiac flow and cardiac electrical activity. The time to loss of all parameters was calculated. Postmortem evaluation allowed for histopathologic evaluation of the oral cavity and gastrointestinal tract to detect potential mucosal damage from the alkaline euthanasia solution. The median time to death was 300 minutes (range, 300 to 360 minutes), median time to respiratory arrest was 30 minutes (range, 30 to 50 minutes), and median time to loss of deep pain response was 30 minutes (range, 20 to 50 minutes). Signs consistent with oral irritation occurred in 4 of 6 (66.7%) lizards, including 2 lizards that exhibited whole-body spasms after euthanasia solution administration. Histopathologic changes indicating peracute mucosal ulceration, suspected to be from caustic causes, were identified in 1 (1/6 [16.7%]) lizard. Transmucosal euthanasia solution administration resulted in clinical euthanasia within 6 hours. This method should be utilized only after premedication with analgesic and/or anesthetic medications due to the potential for acute mucosal ulceration and behaviors that may be distressing in client-owned animals.

Neurobehavioral Progress and Signs of Transition in Children With Prolonged Disorders of Consciousness: A Retrospective Longitudinal Study With the Coma Recovery Scale-Revised

BackgroundResearch on disorders of consciousness in children is scarce and includes disparate and barely comparable participants and assessment instruments and therefore provides inconclusive information on the clinical progress and recovery in this population. This study retrospectively investigated the neurobehavioral progress and the signs of transition between states of consciousness in a group of children admitted to a rehabilitation program either with an unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS). MethodsSystematic weekly assessments were conducted with the Coma Recovery Scale-Revised (CRS-R) until emergence from MCS, discharge, or death. ResultsTwenty-one children, nine admitted with a UWS and 12 admitted in an MCS, were included in the study. Four children with a UWS transitioned to an MCS with a CRS-R of 10 (9.2 to 12.2) by showing visual pursuit, visual fixation, or localization to noxious stimulation. Twelve children emerged from the MCS with a CRS-R of 20.5 (19 to 21.7). Children who emerged from the MCS had had a shorter time postinjury and higher CRS-R at admission, compared with those who did not emerge. ConclusionsAlmost half of the children who were admitted with a UWS transitioned to an MCS, and almost all who were admitted in an MCS emerged from this state. Children who emerged had shorter times since injury and higher scores on the CRS-R at admission, compared with those who did not emerge.