Therapeutic effects of mitoquinol during an acute heat stress challenge in growing barrows.

Study objectives were to determine the effects of mitoquinol (MitoQ, a mitochondrial-targeted antioxidant) on biomarkers of metabolism and inflammation during acute heat stress (HS). Crossbred barrows [n = 32; 59.0 ±â€…5.6 kg body weight (BW)] were blocked by BW and randomly assigned to 1 of 4 environmental-therapeutic treatments: 1) thermoneutral (TN) control (n = 8; TNCon), 2) TN and MitoQ (n = 8; TNMitoQ), 3) HS control (n = 8; HSCon), or 4) HS and MitoQ (n = 8; HSMitoQ). Pigs were acclimated for 6 d to individual pens before study initiation. The trial consisted of two experimental periods (P). During P1 (2 d), pigs were fed ad libitum and housed in TN conditions (20.6 ±â€…0.8 °C). During P2 (24 h), HSCon and HSMitoQ pigs were exposed to continuous HS (35.2 ±â€…0.2 °C), while TNCon and TNMitoQ remained in TN conditions. MitoQ (40 mg/d) was orally administered twice daily (0700 and 1800 hours) during P1 and P2. Pigs exposed to HS had increased rectal temperature, skin temperature, and respiration rate (+1.5 °C, +6.8 °C, and +101 breaths per minute, respectively; P < 0.01) compared to their TN counterparts. Acute HS markedly decreased feed intake (FI; 67%; P < 0.01); however, FI tended to be increased in HSMitoQ relative to HSCon pigs (1.5 kg vs. 0.9 kg, respectively; P = 0.08). Heat-stressed pigs lost BW compared to their TN counterparts (-4.7 kg vs. +1.6 kg, respectively; P < 0.01); however, the reduction in BW was attenuated in HSMitoQ compared to HSCon pigs (-3.9 kg vs. -5.5 kg, respectively; P < 0.01). Total gastrointestinal tract weight (empty tissue and luminal contents) was decreased in HS pigs relative to their TN counterparts (6.2 kg vs. 8.6 kg, respectively; P < 0.01). Blood glucose increased in HSMitoQ relative to HSCon pigs (15%; P = 0.04). Circulating non-esterified fatty acids (NEFA) increased in HS compared to TN pigs (P < 0.01), although this difference was disproportionately influenced by elevated NEFA in HSCon relative to HSMitoQ pigs (251 µEq/L vs. 142 µEq/L; P < 0.01). Heat-stressed pigs had decreased circulating insulin relative to their TN counterparts (47%; P = 0.04); however, the insulin:FI ratio tended to increase in HS relative to TN pigs (P = 0.09). Overall, circulating leukocytes were similar across treatments (P > 0.10). Plasma C-reactive protein remained similar among treatments; however, haptoglobin increased in HS relative to TN pigs (48%; P = 0.03). In conclusion, acute HS exposure negatively altered animal performance, inflammation, and metabolism, which were partially ameliorated by MitoQ.

Heat stress (HS) compromises animal health and productivity, and this causes major economic losses in almost every livestock sector. The negative consequences of HS are thought to originate from intestinal barrier dysfunction and subsequent immune activation. The underlying causes of lost intestinal integrity during HS are likely multifactorial; however, intestinal ischemia, increased accumulation of reactive oxygen species, and the ensuing epithelial oxidative damage might be potential causes. Mitochondria-targeted antioxidants, such as mitoquinol (MitoQ), are probably more effective than traditional dietary antioxidants (i.e., selenium, vitamin E) at alleviating oxidative stress, as they localize and accumulate within the mitochondria, potentiating their antioxidant activity. Thus, the present study aimed to investigate MitoQ's role during a thermal event in growing pigs. Herein, HS increased all body temperature indices, decreased feed intake (FI), and induced substantial body weight (BW) loss. Interestingly, the reduction in FI and BW was less dramatic in pigs receiving MitoQ. Changes in circulating metabolism and the acute phase response were observed due to the HS challenge; however, contrary to our expectations, these changes were not offset by MitoQ administration. Although our results suggest a positive MitoQ effect on growth performance, future studies are needed to corroborate the replicability of this response during HS.

Turning down the body heat: A novel mechanism for TRPV1 antagonist-induced hyperthermia.

While effective analgesics, TRPV1 antagonists can dangerously alter thermoregulation. In this issue of Neuron, Huang et al.1 demonstrate that interaction with the S4-S5 linker of TRPV1 determines whether an antagonist affects core body temperature, with promising implications for analgesic development.

Identification of hypothermia-inducing neurons in the preoptic area and activation of them by isoflurane anesthesia and central injection of adenosine.

Hibernation and torpor are not passive responses caused by external temperature drops and fasting but are active brain functions that lower body temperature. A population of neurons in the preoptic area was recently identified as such active torpor-regulating neurons. We hypothesized that the other hypothermia-inducing maneuvers would also activate these neurons. To test our hypothesis, we first refined the previous observations, examined the brain regions explicitly activated during the falling phase of body temperature using c-Fos expression, and confirmed the preoptic area. Next, we observed long-lasting hypothermia by reactivating torpor-tagged Gq-expressing neurons using the activity tagging and DREADD systems. Finally, we found that about 40-60% of torpor-tagged neurons were activated by succeeding isoflurane anesthesia and by icv administration of an adenosine A1 agonist. Isoflurane-induced and central adenosine-induced hypothermia is, at least in part, an active process mediated by the torpor-regulating neurons in the preoptic area.

Effects of supplemental citrulline on thermal and intestinal morphology parameters during heat stress and feed restriction in growing pigs.

Study objectives were to characterize the effects of citrulline (CIT) on physiological and intestinal morphology metrics during heat stress (HS) and feed restriction. Forty crossbred gilts (30 ±â€…2 kg body weight [BW]) were assigned to one of five treatments: (1) thermoneutral (TN) fed ad libitum (AL) with control (CON) supplement (TNAL; n = 8), (2) TN pair-fed (PF) with CON (PF-CON; n = 8), (3) TN PF with CIT (PF-CIT; n = 8), (4) HS AL with CON (HS-CON; n = 8), and (5) HS AL with CIT (HS-CIT; n = 8). During the period (P) 1 (7 d), pigs were in TN conditions (23.6 °C) and fed AL their respective supplemental treatments. During P2 (2.5 d), HS-CON and HS-CIT pigs were fed AL and exposed to cyclical HS (33.6 to 38.3 °C), while TNAL, PF-CON, and PF-CIT remained in TN and were fed either AL or PF to their HS counterparts. Citrulline (0.13 g/kg BW) was orally administered twice daily during P1 and P2. HS increased rectal temperature (Tr), skin temperature (Ts), and respiration rate (RR) relative to TN pigs (0.8 °C, 4.7 °C, and 47 breaths/min, respectively; P < 0.01). However, HS-CIT had decreased RR (7 breaths/min, P = 0.04) and a tendency for decreased Tr (0.1 °C, P = 0.07) relative to HS-CON pigs. During P2, HS pigs had decreased feed intake (22%; P < 0.01) and a tendency for decreased average daily gain (P = 0.08) relative to TNAL pigs, and by experimental design, PF pigs followed this same pattern. Circulating lipopolysaccharide-binding protein tended to be decreased (29%; P = 0.08) in PF relative to TNAL pigs and was increased (41%; P = 0.03) in HS compared to PF pigs. Jejunum villus height was decreased in PF relative to TNAL pigs (15%; P = 0.03); however, CIT supplementation improved this metric during feed restriction (16%; P = 0.10). Jejunum mucosal surface area decreased in PF (16%; P = 0.02) and tended to decrease in HS (11%; P = 0.10) compared to TNAL pigs. Ileum villus height and mucosal surface area decreased in HS compared to TNAL pigs (10 and 14%, respectively; P ≤ 0.04), but both parameters were rescued by CIT supplementation (P ≤ 0.08). Intestinal myeloperoxidase and goblet cell area remained similar among treatments and intestinal segments (P > 0.24). In summary, CIT supplementation slightly improved RR and Tr during HS. Feed restriction and HS differentially affected jejunum and ileum morphology and while CIT ameliorated some of these effects, the benefit appeared dependent on intestinal section and stressor type.

Heat stress (HS) negatively affects animal health and production efficiency and is a significant economic burden to global animal agriculture. Although the mechanisms responsible for reduced animal productivity during HS are complex and multifaceted, increasing evidence points to decreased intestinal barrier function as an important mediator of this response. Furthermore, HS causes a voluntary reduction in feed intake, and feed restriction independently induces gastrointestinal hyperpermeability. Loss of intestinal barrier integrity facilitates bacteria translocation across the epithelium into local and systemic circulation, thus initiating an immune response. Dietary citrulline has been shown to support gut health by improving intestinal barrier integrity and modulating intestinal inflammation. Therefore, the current study investigated the effects of citrulline supplementation on physiological and intestinal morphology parameters in heat-stressed and feed-restricted growing pigs. Herein, citrulline supplementation reduced respiration rate and rectal temperature in pigs exposed to the thermal load. Heat stress and feed restriction compromised small intestinal morphology, and while supplementing citrulline improved some of these parameters, the effects depended on the intestinal region and stressor type. Additional research is needed to evaluate the potential effects of citrulline supplementation on gut health during HS or nutrient restriction.

Influence of fentanyl, medetomidine-fentanyl or acepromazine-fentanyl premedication on oesophageal and rectal temperature in dogs under anaesthesia.

OBJECTIVE: To compare changes in oesophageal (T-Oeso) and rectal (T-Rec) temperature in dogs during general anaesthesia and premedicated with fentanyl, medetomidine-fentanyl or acepromazine-fentanyl. STUDY DESIGN: Prospective, randomized, blind clinical study. ANIMALS: A total of 120 healthy dogs, aged 2-10 years and weighing 5-20 kg. METHODS: Dogs were randomly allocated to one of three groups. Animals of F group were premedicated with fentanyl (0.01 mg kg-1), MF group with medetomidine (0.005 mg kg-1) and fentanyl (0.01 mg kg-1) and AF group with acepromazine (0.01 mg kg-1) and fentanyl (0.01 mg kg-1). Anaesthesia was induced with propofol and maintained with isoflurane in oxygen-air mixture. Fentanyl was administered continuously (0.01 mg kg-1 hour-1). The T-Oeso, T-Rec and ambient temperatures were recorded after induction (T0) and subsequently at 10 minute intervals for 60 minutes (T10-T60). Data were analysed using anova or their non-parametric equivalents (p < 0.05). RESULTS: Median T-Oeso was significantly higher in MF group between T0-T20 compared with other groups. Median T-Oeso significantly decreased in F group from 38.0 °C (T0) to 37.4 °C (T30), 37.1 °C (T40), 36.9 °C (T50) and 36.6 °C (T60), in MF group from 38.3 °C (T0) to 37.7 °C (T30), 37.5 °C (T40), 37.2 °C (T50) and 37.1 °C (T60) and in AF group from 37.7 °C (T0) to 37.3 °C (T40), 37.2 °C (T50) and 37.1 °C (T60). The T-Rec significantly decreased in F group from 38.0 °C (T0) to 37.4 °C (T40), 37.2 °C (T50) and 36.9 °C (T60), in MF group from 38.3 °C (T0) to 37.5 °C (T50) and 37.4 °C (T60) and in AF group from 38.2 °C (T0) to 37.6 °C (T40), 37.5 °C (T50) and 37.4 °C (T60). CONCLUSIONS AND CLINICAL RELEVANCE: Premedication with fentanyl, medetomidine-fentanyl or acepromazine-fentanyl in the doses used decreased the T-Oeso and T-Rec. The T-Oeso at the beginning of anaesthesia was higher after premedication with medetomidine-fentanyl. However, this difference was not clinically significant.

Hemodynamic Parameters in Spontaneously Hypertensive Rats with Obesity and Chemically Induced Colitis during Probiotic Therapy.

We studied the dynamics of the main hemodynamic parameters in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with visceral obesity and chemically induced colitis (CIC) against the background of probiotic therapy. Systolic BP, HR, and body temperature were recorded over 36 days using a wireless telemetry system. During 8 days (3 days before CIC induction and until the end of the experiment) the animals were intragastrically administered a probiotic based on Lactobacillus delbrueckii D5 strain. At baseline, systolic BP was significantly higher in the SHR group, while HR and body temperature did not differ in SHR and WKY rats. On day 8 after CIC induction, systolic BP, HR, and body temperature in SHR were significantly increased in comparison with the initial values. In the group of WKY rats, all indices at the end of the experiment remained at the initial levels. Probiotic therapy in SHR, in contrast to WKY rats, did not lead to normalization of body temperature and hemodynamic disorders resulting from CIC.

Ammonium chloride-induced hypothermia is attenuated by transient receptor potential channel vanilloid-1, but augmented by ankyrin-1 in rodents.

AIMS: Systemic administration of ammonium chloride (NH4Cl), an acidifying agent used in human patients and experimental conditions, causes hypothermia in mice, however, the mechanisms of the thermoregulatory response to NH4Cl and whether it develops in other species remained unknown. MAIN METHODS: We studied body temperature (Tb) changes in rats and mice induced by intraperitoneal administration of NH4Cl after blockade of transient receptor potential vanilloid-1 (TRPV1) or ankyrin-1 (TRPA1) channels. KEY FINDINGS: In rats, NH4Cl decreased Tb by 0.4-0.8°C (p < 0.05). The NH4Cl-induced hypothermia also developed in Trpv1 knockout (Trpv1-/-) and wild-type (Trpv1+/+) mice, however, the Tb drop was exaggerated in Trpv1-/- mice compared to Trpv1+/+ controls with maximal decreases of 4.0 vs. 2.1°C, respectively (p < 0.05). Pharmacological blockade of TRPV1 channels with AMG 517 augmented the hypothermic response to NH4Cl in genetically unmodified mice and rats (p < 0.05 for both). In contrast, when NH4Cl was infused to mice genetically lacking the TRPA1 channel, the hypothermic response was significantly attenuated compared to wild-type controls with maximal mean Tb difference of 1.0°C between the genotypes (p = 0.008). Pretreatment of rats with a TRPA1 antagonist (A967079) also attenuated the NH4Cl-induced Tb drop with a maximal difference of 0.7°C between the pretreatment groups (p = 0.003). SIGNIFICANCE: TRPV1 channels limit, whereas TRPA1 channels exaggerate the development of NH4Cl-induced hypothermia in rats and mice, but other mechanisms are also involved. Our results warrant for regular Tb control and careful consideration of NH4Cl treatment in patients with TRPA1 and TRPV1 channel dysfunctions.

Genotoxicity and safety pharmacology of the rVSVInd(GML)-mspSGtc vaccine against SARS-CoV-2 in Sprague-Dawley rats and Beagle dogs.

The emergence of coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a pandemic, prompting rapid vaccine development. Although vaccines are effective, the occurrence of rare adverse events following vaccination highlights the necessity of determining whether the benefits outweigh the risks posed by the infection itself. The recombinant Vesicular Stomatitis Virus (rVSV) platform is a promising vector for vaccines against emerging viruses. However, limited studies have evaluated the genotoxicity and safety pharmacology of this viral vector vaccine, which is crucial to ensure the safety of vaccines developed using this platform. Hence, the present study aimed to assess the genotoxicity and safety pharmacology of the rVSVInd(GML)-mspSGtc COVID-19 vaccine using micronucleus and comet assays, as well as neurobehavioral, body temperature, respiratory, and cardiovascular assessments in Sprague-Dawley rats and beagle dogs. The intramuscular administration of rVSVInd(GML)-mspSGtc at doses up to 1.5 × 109 PFU/animal did not increase the number of bone marrow micronucleated polychromatic erythrocytes or cause liver DNA damage. Additionally, it had no significant impact on neurobehavioral functions in rats and showed marginal temporary changes in body temperature, respiratory rate, heart rate, and electrocardiogram parameters in rats and dogs, all of which resolved within 24 h. Overall, following genotoxicity and pharmacological safety assessments, rVSVInd(GML)-mspSGtc displayed no notable systemic adverse effects in rats and dogs, suggesting its potential as a vaccine candidate for human clinical trials.

Randomized comparison between a forced air system and warm water bath for resuscitation of neonatal hypothermic calves with or without oral administration of caffeine.

BACKGROUND: Hypothermia is a cause of neonatal calf death in cold climates. Practical and effective rewarming methods are important for bovine health within affected regions. HYPOTHESIS/OBJECTIVES: To compare the rewarming rate and blood analytes (glucose, lactate, and cortisol) of calves resuscitated with forced air with warm water bath, with or without oral administration of caffeine. ANIMALS: Twenty healthy neonatal Holstein bull calves. METHODS: In this randomized, prospective study, calves born healthy and without history of dystocia were cooled to 32°C rectal temperature then thermally resuscitated using either forced air rewarming or warm water bath (40°C) with or without oral administration of caffeine. Rectal temperatures were used to quantify recovery rate. Measurements of glucose, lactate, and cortisol were recorded for every 2°C change in rectal temperature. RESULTS: Rectal temperature decline (0.03°C per minute) and total cooling time (191.0 ± 33.3 minutes) did not significantly differ among treatment groups. Calves were successfully resuscitated to 38°C by either method. Time required to euthermia using warm water was significantly faster (0.1°C per minute; 64.3 ± 17.8 minute; P < .05) than forced air (0.05°C per minute; 123.1 ± 20.0 minutes). Caffeine had no significant effect on resuscitation rate (P = .14; 95% CI, -0.002 to 0.024) in either treatment; however, caffeine was associated with reduced time to euthermia by 8.3 and 10.8 minutes, respectively. Changes in metabolic variables (glucose, lactate, and cortisol), were inversely related to rectal temperature with no statistical significance among rewarming methods. CONCLUSIONS AND CLINICAL IMPORTANCE: Although warm water submersion is faster, forced air rewarming is an effective alternative for restoration of euthermia.

Hypothermia as potential therapeutic approach to attenuating soman-induced seizure, neuropathology, and mortality with an adenosine A1 receptor agonist and body cooling.

Organophosphorus nerve agents, such as soman (GD), produce excitotoxic effects resulting in sustained status epilepticus (SSE) and brain damage. Previous work shows that neuronal inhibitory effects of A1 adenosine receptor (A1AR) agonists, such as N6- Bicyclo (2.2.1)-hept-2-yl-5'-chloro-5'-deoxyadenosine (Cl-ENBA), suppresses GD-induced SSE and improves neuropathology. Some other physiologic effects of these agonists are hypothermia, hypotension, and sedation. Hypothermia may also shield the brain from injury by slowing down chemical insults, lessening inflammation, and contributing to improved neurological outcomes. Therefore, we attempted to isolate the hypothermic effect from ENBA by assessing the neuroprotective efficacy of direct surface body cooling in a rat GD-induced SSE model, and comparing the effects on seizure termination, neuropathology, and survival. Male rats implanted with a body temperature (Tb) transponder and electroencephalographic (EEG) electrodes were primed with asoxime (HI-6), exposed to GD 30 min later, and then treated with Cl-ENBA or had Tb lowered directly via body cooling at 30 min after the onset of seizure activity. Afterwards, they were either allowed to develop hypothermia as expected, or received thermal support to maintain normothermic Tb for a period of 6-h. Neuropathology was assessed at 24 h. Regardless of Cl-ENBA or surface cooling, all hypothermic GD-exposed groups had significantly improved 24-h survival compared to rats with normothermic Tb (81% vs. 39%, p < 0.001). Cl-ENBA offered neuroprotection independently of hypothermic Tb. While hypothermia enhanced the overall efficacy of Cl-ENBA by improving survival outcomes, body cooling didn't reduce seizure activity or neuropathology following GD-induced SSE.

In ovo feeding of α-ketoglutaric acid improves hepatic antioxidant-gene expression, plasma antioxidant activities and decreases body temperature without affecting broiler body weight under cyclic heat stress.

The broiler industry is adversely affected by the rise in global temperature. This study investigated the effects of in ovo feeding of α-ketoglutaric acid (AKG) on growth performance, organ weight, plasma metabolite, plasma oxidative stress, rectal temperature (RT), and hepatic mRNA expression of antioxidant-related genes in Arbor Acres broilers subjected to cyclic heat stress (HS). Three hundred fifty fertile eggs during incubation were divided into 5 groups according to AKG concentrations and temperature conditions. After dissolving AKG in distilled water at 0, 0.5, 1.0, and 1.5, 0% AKG was in ovo administered to 2 of the 5 groups whereas the remaining 3 groups received 0.5, 1.0, and 1.5%, respectively. From d 29 to 34 of age, 4 groups of birds received heat stress (HS) at 31°C ± 1°C for 6 h per day while the other group was kept at room temperature (21°C ± 1°C; NT). So, the 5 treatment groups were: 1) 0AKG-NT, where chicks hatched from eggs receiving 0% AKG were reared under thermoneutral conditions. 2) 0AKG-HS, where chicks hatched from eggs receiving 0% AKG were reared under cyclic HS conditions. 3) 0.5AKG-HS, where chicks hatched from eggs receiving 0.5% AKG were reared under cyclic HS conditions. 4) 1.0AKG-HS, where chicks hatched from eggs receiving 1.0% AKG were reared under cyclic HS conditions. 5) 1.5AKG-HS, where chicks hatched from eggs receiving 1.5% AKG were reared under cyclic HS conditions. HS significantly reduced body weight change (ΔBW %) and average daily gain (ADG) without affecting average daily feed intake (ADFI). Feed conversion ratio (FCR) was significantly increased (P = 0.003) in all HS-treated groups. A significant linear decrease in the final RT (P = 0.005) and a change in RT (P = 0.003) were detected with increasing AKG concentration. Total antioxidant capacity (P = 0.029) and antioxidant balance (P = 0.001) in plasma increased linearly with increasing AKG concentration whereas malondialdehyde concentrations were linearly decreased (P = 0.001). Hepatic gene expression of CAT (P = 0.026) and GPX1 (P = 0.001) were dose-dependently upregulated while nicotinamide adenine dinucleotide phosphate oxidase (NOX)1, NOX4, and heat shock protein (HSP)70 were linearly downregulated (P < 0.05). Hence, in ovo injection of AKG was effective in mitigating HS-induced oxidative stress without attenuating the adverse effects on broiler growth.

Acute experimental inflammation in healthy women attenuates empathy for psychological pain.

Administration of low-dose lipopolysaccharide (LPS) to healthy humans is a translational approach to analyze the effects of acute systemic inflammation and sickness behavior. Although studies documented that LPS-induced inflammation can alter social behavior, its impact on empathy remains poorly understood. In this double-blind, placebo-controlled study, 52 healthy female volunteers received an intravenous injection of either LPS (0.4 ng/kg body weight) or placebo and completed the Social Interaction Empathy Task (SIET) two hours after injection. Physiological responses (blood pressure, heart rate, body temperature, cytokines, cortisol) were analyzed along with sickness symptoms and mood before and after LPS or placebo administration. LPS application led to significant increases in plasma cytokines and sickness symptoms as well as low mood. Moreover, volunteers receiving LPS showed significantly less empathy for other's psychological pain than those who received placebo. Furthermore, LPS-injected volunteers with more severe sickness symptoms displayed higher pain ratings in the first-person perspective. Thus, low-grade inflammation reduces empathy for other's psychological pain which might reflect an adaptive strategy to save energy by not responding empathetically when sick oneself.

TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception.

Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1-/-, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, a TRPV1 antagonist we discovered, is effective against inflammatory pain but devoid of binding to the S4-S5 linker and inducing CBT changes. These findings implicate that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, opening avenues for the development of non-opioid analgesics without affecting CBT.

Effect of platelet-activating factor on food intake, cloacal temperature, voluntary activity and crop emptying rate in chicks.

Platelet-activating factor (PAF) plays a significant role in several leucocyte functions, including platelet aggregation and inflammation. Additionally, PAF has a role in the behavioral and physiological changes in mammals. However, the effect of PAF has not been well studied in birds. Therefore, the study aimed to determine if PAF affects feeding behavior, voluntary activity, cloacal temperature, and feed passage through the digestive tract in chicks (Gallus gallus). We also studied the involvement of PAF in the innate immune system induced by lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria. Both intraperitoneal (IP) and intracerebroventricular (ICV) injections of PAF significantly decreased food intake. IP injection of PAF significantly decreased voluntary activity and slowed the feed passage from the crop, whereas ICV injection had no effect. Conversely, ICV injection of PAF significantly increased the cloacal temperature, but IP injection had no effect. The IP injection of LPS significantly reduced the mRNA expression of lysophosphatidylcholine acyltransferase 2, an enzyme responsible for PAF production in the heart and pancreas. On the other hand, LPS significantly increased the mRNA expression of the PAF receptor in the peripheral organs. The present study shows that PAF influences behavioral and physiological responses and is related to the response against bacterial infections in chicks.

A randomized controlled trial of oral antipyretic treatment to reduce overheating during exercise in adults with multiple sclerosis.

BACKGROUND: Some people with multiple sclerosis (pwMS) avoid exercise due to overheating. Evidence from a variety of cooling treatments shows benefits for pwMS. OBJECTIVE: Conduct a randomized controlled trial of antipyretic treatment before exercise in pwMS. METHODS: Adults over age 18 diagnosed with relapsing-remitting MS reporting heat sensitivity during exercise were randomly assigned to one of six sequences counterbalancing aspirin, acetaminophen, placebo. At each of three study visits separated by ≥ one week, participants received 650-millograms of aspirin, acetaminophen, or placebo before completing a maximal exercise test. Primary outcomes were body temperature change and total time-to-exhaustion (TTE), secondary outcomes were physiological and patient-reported outcomes (PROs). RESULTS: Sixty participants were enrolled and assigned to treatment sequence; 37 completed ≥ one study visit. After controlling for order effects, we found that body temperature increase was reduced after aspirin (+ 0.006 ± 0.32 degrees Fahrenheit, p < 0.001) and after acetaminophen (+ 0.31 ± 0.35; p = 0.004) compared to placebo (+ 0.68 ± 0.35). TTE after aspirin (331.6 ± 76.6 s) and acetaminophen (578.2 ± 82.1) did not differ significantly from placebo (551.0 ± 78.4; p's > 0.05). Aspirin benefited all secondary outcomes compared to placebo (all p's < 0.001); acetaminophen showed broadly consistent benefits. CONCLUSION: These results support antipyretic treatment as effective for reducing overheating during exercise in pwMS and failed to support antipyretics for increasing TTE in the context of a maximal exercise test. Benefits were shown for physiological markers of exercise productivity and PROs of fatigue, pain, and perceived exertion.

A Comparison of Three Anesthetic Drug Combinations for Use in Inducing Surgical Anesthesia in Female Guinea Pigs (Cavia porcellus).

Guinea pigs are often used in translational research, but providing them with safe and effective anesthesia is a challenge. Common methods like inhalant anesthesia and injectable ketamine/xylazine induce surgical anesthesia but can negatively affect cardiovascular, respiratory, and thermoregulatory systems and complicate the interpretation of research outcomes. Several alternative anesthetic regimens have been investigated, but none have consistently achieved a surgical plane of anesthesia. Therefore, identifying an anesthetic regimen that achieves a stable state of the surgical plane of anesthesia while preserving cardiorespiratory function would be a valuable contribution. To address this issue, we compared the efficacy of 3 anesthetic combinations in female Dunkin-Hartley guinea pigs: 1) alfaxalone, dexmedetomidine, and fentanyl (ADF); 2) alfaxalone, midazolam, and fentanyl (AMF); and 3) alfaxalone, midazolam, fentanyl, and isoflurane (AMFIso). We monitored anesthetic depth, heart rate, oxygenation, respiratory rate, respiratory effort, blood pressure, and body temperature every 15 min from injection to recovery. We also recorded the time to loss of righting reflex, duration of anesthesia, and time to achieve a surgical plane. The results showed no statistically significant differences in induction and recovery times among the groups. In the AMFIso group, 100% of the animals achieved a surgical plane of anesthesia, whereas only 10% of the animals in the AMF group reached that level. None of the animals in ADF group reached a surgical plane of anesthesia. Respiratory rate was significantly lower in the AMFIso as compared with the ADF group (P < 0.001) but was not different between the AMF and ADF groups. Temperature was significantly lower in the AMFIso group as compared with both the ADF and AMF groups (P < 0.001). In conclusion, both combinations of solely injectable anesthetics assessed in this study can be used for short, nonpainful procedures without significant cardiorespiratory depression. However, for mildly to moderately painful surgical procedures, the addition of an inhalant anesthetic like isoflurane is necessary for female guinea pigs.

The open field assay is influenced by room temperature and by drugs that affect core body temperature.

Background: The open field assay is used to study anxiety-related traits and anxiolytic drugs in rodents. This assay entails measuring locomotor activity and time spent in the center of a chamber that is maintained at ambient room temperature. However, the ambient temperature in most laboratories varies daily and seasonally and can differ between buildings. We sought to evaluate how varying ambient temperature and core body temperature (CBT) affected open field locomotor activity and center time of male wild-type (WT, C57BL/6) and Transient Receptor Potential Subfamily M Member 8 ( Trpm8) knock-out ( Trpm8 -/- ) mice. TRPM8 is an ion channel that detects cool temperatures and is activated by icilin. Methods: Mice were placed in the open field at 4°C and 23°C for 30 minutes. Distance traveled and time spent in the center were measured. Mice were injected with icilin, M8-B, diazepam, or saline, and changes in activity level were recorded. Results: The cooling agent icilin increased CBT and profoundly reduced distance traveled and center time of WT mice relative to controls. Likewise, cooling the ambient temperature to 4°C reduced distance traveled and center time of WT mice relative to Trpm8 -/- mice. Conversely, the TRPM8 antagonist (M8-B) reduced CBT and increased distance traveled and center time of WT mice when tested at 4°C. The TRPM8 antagonist (M8-B) had no effect on CBT or open field behavior of Trpm8 -/- mice. The anxiolytic diazepam reduced CBT in WT and Trpm8 -/- mice. When tested at 4°C, diazepam increased distance traveled and center time in WT mice but did not alter open field behavior of Trpm8 -/- mice. Conclusions: Environmental temperature and drugs that affect CBT can influence locomotor behavior and center time in the open field assay, highlighting temperature (ambient and core) as sources of environmental and physiologic variability in this commonly used behavioral assay.

Effect of Acetaminophen on Endurance Cycling Performance in Trained Triathletes in Hot and Humid Conditions.

PURPOSE: The effect of acetaminophen (ACT, also known as paracetamol) on endurance performance in hot and humid conditions has been shown previously in recreationally active populations. The aim of this study was to determine the effect of ACT on physiological and perceptual variables during steady-state and time-trial cycling performance of trained triathletes in hot and humid conditions. METHODS: In a randomized, double-blind crossover design, 11 triathletes completed ∼60 minutes steady-state cycling at 63% peak power output followed by a time trial (7 kJ·kg body mass-1, ∼30 min) in hot and humid conditions (∼30°C, ∼69% relative humidity) 60 minutes after consuming either 20 mg·kg body mass-1 ACT or a color-matched placebo. Time-trial completion time, gastrointestinal temperature, skin temperature, thermal sensation, thermal comfort, rating of perceived exertion, and fluid balance were recorded throughout each session. RESULTS: There was no difference in performance in the ACT trial compared with placebo (P = .086, d = 0.57), nor were there differences in gastrointestinal and skin temperature, thermal sensation and comfort, or fluid balance between trials. CONCLUSION: In conclusion, there was no effect of ACT (20 mg·kg body mass-1) ingestion on physiology, perception, and performance of trained triathletes in hot and humid conditions, and existing precooling and percooling strategies appear to be more appropriate for endurance cycling performance in the heat.

Caffeine and MDMA (Ecstasy) Exacerbate ER Stress Triggered by Hyperthermia.

Drugs of abuse can cause local and systemic hyperthermia, a known trigger of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Another trigger of ER stress and UPR is ER calcium depletion, which causes ER exodosis, the secretion of ER-resident proteins. In rodent models, club drugs such as 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') can create hyperthermic conditions in the brain and cause toxicity that is affected by the environmental temperature and the presence of other drugs, such as caffeine. In human studies, MDMA stimulated an acute, dose-dependent increase in core body temperature, but an examination of caffeine and MDMA in combination remains a topic for clinical research. Here we examine the secretion of ER-resident proteins and activation of the UPR under combined exposure to MDMA and caffeine in a cellular model of hyperthermia. We show that hyperthermia triggers the secretion of normally ER-resident proteins, and that this aberrant protein secretion is potentiated by the presence of MDMA, caffeine, or a combination of the two drugs. Hyperthermia activates the UPR but the addition of MDMA or caffeine does not alter the canonical UPR gene expression despite the drug effects on ER exodosis of UPR-related proteins. One exception was increased BiP/GRP78 mRNA levels in MDMA-treated cells exposed to hyperthermia. These findings suggest that club drug use under hyperthermic conditions exacerbates disruption of ER proteostasis, contributing to cellular toxicity.

The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway.

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam, or etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ∼0.4°C from 10 min postinfusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ∼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ∼50% in both); all these changes were completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response.NEW & NOTEWORTHY An association between central cholecystokinin signaling and the cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of cyclooxygenase. We also show that the activation of cyclooxygenase-2 is required for the hyperthermic effect of cholecystokinin and that cholecystokinin is a modulator of endotoxin-induced fever.