Evolutionary deletions within the SARS-CoV-2 genome as signature trends for virus fitness and adaptation.

Coronaviruses are large RNA viruses that can infect and spread among humans and animals. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019, has evolved since its first detection in December 2019. Deletions are a common occurrence in SARS-CoV-2 evolution, particularly in specific genomic sites, and may be associated with the emergence of highly competent lineages. While deletions typically have a negative impact on viral fitness, some persist and become fixed in viral populations, indicating that they may confer advantageous benefits for the virus's adaptive evolution. This work presents a literature review and data analysis on structural losses in the SARS-CoV-2 genome and the potential relevance of specific signatures for enhanced viral fitness and spread.

Cannabidiol induces systemic analgesia through activation of the PI3Kγ/nNOS/NO/KATP signaling pathway in neuropathic mice. A KATP channel S-nitrosylation-dependent mechanism.

BACKGROUND: Cannabidiol (CBD) is the second most abundant pharmacologically active component present in Cannabis sp. Unlike Δ-9-tetrahydrocannabinol (THC), it has no psychotomimetic effects and has recently received significant interest from the scientific community due to its potential to treat anxiety and epilepsy. CBD has excellent anti-inflammatory potential and can be used to treat some types of inflammatory and neuropathic pain. In this context, the present study aimed to evaluate the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain and determine the endogenous mechanisms involved with this analgesia. METHODS: Neuropathic pain was induced by sciatic nerve constriction surgery, and the nociceptive threshold was measured using the paw compression test in mice. RESULTS: CBD produced dose-dependent antinociception after intraperitoneal injection. Selective inhibition of PI3Kγ dose-dependently reversed CBD-induced antinociception. Selective inhibition of nNOS enzymes reversed the antinociception induced by CBD, while selective inhibition of iNOS and eNOS did not alter this antinociception. However, the inhibition of cGMP production by guanylyl cyclase did not alter CBD-mediated antinociception, but selective blockade of ATP-sensitive K+ channels dose-dependently reversed CBD-induced antinociception. Inhibition of S-nitrosylation dose-dependently and completely reversed CBD-mediated antinociception. CONCLUSION: Cannabidiol has an antinociceptive effect when administered systemically and this effect is mediated by the activation of PI3Kγ as well as by nitric oxide and subsequent direct S-nitrosylation of KATP channels on peripheral nociceptors.

Nitric oxide and potassium channels but not opioid and cannabinoid receptors mediate tramadol-induced peripheral antinociception in rat model of paw pressure withdrawal.

Tramadol, an analgesic classified as an "atypical opioid", exhibits both opioid and non-opioid mechanisms of action. This study aimed to explore these mechanisms, specifically the opioid-, cannabinoid-, nitric oxide-, and potassium channel-based mechanisms, which contribute to the peripheral antinociception effect of tramadol, in an experimental rat model. The nociceptive threshold was determined using paw pressure withdrawal. To examine the mechanisms of action, several substances were administered intraplantarly: naloxone, a non-selective opioid antagonist (50 µg/paw); AM251 (80 µg/paw) and AM630 (100 µg/paw) as the selective antagonists for types 1 and 2 cannabinoid receptors, respectively; nitric oxide synthase inhibitors L-NOArg, L-NIO, L-NPA, and L-NIL (24 µg/paw); and the enzyme inhibitors of guanylatocyclase and phosphodiesterase of cGMP, ODQ, and zaprinast. Additionally, potassium channel blockers glibenclamide, tetraethylammonium, dequalinium, and paxillin were used. The results showed that opioid and cannabinoid receptor antagonists did not reverse tramadol's effects. L-NOarg, L-NIO, and L-NPA partially reversed antinociception, while ODQ completely reversed, and zaprinast enhanced tramadol's antinociception effect. Notably, glibenclamide blocked tramadol's antinociception in a dose-dependent manner. These findings suggest that tramadol's peripheral antinociception effect is likely mediated by the nitrergic pathway and sensitive ATP potassium channels, rather than the opioid and cannabinoid pathways.

Endogenous Cholinergic System Involved in Peripheral Analgesic Control in Mice Is Activated by TNF-α, CXCL-1, and IL-1ß.

INTRODUCTION: Tissue injury results in the release of inflammatory mediators, including a cascade of algogenic substances, which contribute to the development of hyperalgesia. During this process, endogenous analgesic substances are peripherally released to counterbalance hyperalgesia. The present study aimed to investigate whether inflammatory mediators TNF-α, IL-1ß, CXCL1, norepinephrine (NE), and prostaglandin E2 (PGE2) may be involved in the deflagration of peripheral endogenous modulation of inflammatory pain by activation of the cholinergic system. METHODS: Male Swiss mice were subjected to paw withdrawal test. All the substances were injected via the intraplantar route. RESULTS: The main findings of this study were as follows: (1) carrageenan (Cg), TNF-α, CXCL-1, IL1-ß, NE, and PGE2 induced hyperalgesia; (2) the acetylcholinesterase enzyme inhibitor, neostigmine, reversed the hyperalgesia observed after Cg, TNF-α, CXCL-1, and IL1-ß injection; (3) the non-selective muscarinic receptor antagonist, atropine, and the selective muscarinic type 1 receptor (m1AChr) antagonist, telenzepine, potentiated the hyperalgesia induced by Cg and CXCL-1; (4) mecamylamine, a non-selective nicotinic receptor antagonist, potentiated the hyperalgesia induced by Cg, TNF-α, CXCL-1, and IL1-ß; (5) Cg, CXCL-1, and PGE2 increased the expression of the m1AChr and nicotinic receptor subunit α4protein. CONCLUSION: These results suggest that the cholinergic system may modulate the inflammatory pain induced by Cg, PGE2, TNF-α, CXCL-1, and IL1-ß.

Peripherally injected canabidiol reduces neuropathic pain in mice: Role of the 5-HT1A and TRPV1 receptors.

Cannabidiol (CBD) is the most abundant non-psychoactive component found in plants of the genus Cannabis. Its analgesic effect for the treatment of neuropathy has been widely studied. However, little is known about its effects in the acute treatment when Cannabidiol is administered peripherally. Because of that, this research was aimed to evaluate the antinociceptive effects of the CBD when administered peripherally for the treatment of acute neuropathic pain and check the involvement of the 5-HT1A and the TRPV1 receptors in this event. Neuropathic pain was induced with the constriction of the sciatic nerve while the nociceptive threshold was measured using the pressure test of the mouse paw. The technique used proved to be efficient to induce neuropathy, and the CBD (5, 10 and 30 µg/paw) induced the antinociception in a dosage-dependent manner. The dosage used that induced a more potent effect (30 µg/paw), did not induce a systemic response, as demonstrated by both the motor coordination assessment test (RotaRod) and the antinociceptive effect restricted to the paw treated with CBD. The administration of NAN-190 (10 µg/paw), a selective 5-HT1A receptor antagonist, and SB-366791 (16 µg/paw), a selective TRPV1 antagonist, partially reversed the CBD-induced antinociception. The results of the research suggest that the CBD produces the peripheral antinociception during the acute treatment of the neuropathic pain and it partially involved the participation of the 5-HT1A and TRPV1 receptors.

Spatiotemporal evolution of COVID-19 in Portugal's Mainland with self-organizing maps.

BACKGROUND: Self-Organizing Maps (SOM) are an unsupervised learning clustering and dimensionality reduction algorithm capable of mapping an initial complex high-dimensional data set into a low-dimensional domain, such as a two-dimensional grid of neurons. In the reduced space, the original complex patterns and their interactions can be better visualized, interpreted and understood. METHODS: We use SOM to simultaneously couple the spatial and temporal domains of the COVID-19 evolution in the 278 municipalities of mainland Portugal during the first year of the pandemic. Temporal 14-days cumulative incidence time series along with socio-economic and demographic indicators per municipality were analyzed with SOM to identify regions of the country with similar behavior and infer the possible common origins of the incidence evolution. RESULTS: The results show how neighbor municipalities tend to share a similar behavior of the disease, revealing the strong spatiotemporal relationship of the COVID-19 spreading beyond the administrative borders of each municipality. Additionally, we demonstrate how local socio-economic and demographic characteristics evolved as determinants of COVID-19 transmission, during the 1st wave school density per municipality was more relevant, where during 2nd wave jobs in the secondary sector and the deprivation score were more relevant. CONCLUSIONS: The results show that SOM can be an effective tool to analysing the spatiotemporal behavior of COVID-19 and synthetize the history of the disease in mainland Portugal during the period in analysis. While SOM have been applied to diverse scientific fields, the application of SOM to study the spatiotemporal evolution of COVID-19 is still limited. This work illustrates how SOM can be used to describe the spatiotemporal behavior of epidemic events. While the example shown herein uses 14-days cumulative incidence curves, the same analysis can be performed using other relevant data such as mortality data, vaccination rates or even infection rates of other disease of infectious nature.

Evidence for the involvement of opioid and cannabinoid systems in the peripheral antinociception mediated by resveratrol.

Despite all the development of modern medicine, around 100 compounds derived from natural products were undergoing clinical trials only at the end of 2013. Among these natural substances in clinical trials, we found the resveratrol (RES), a pharmacological multi-target drug. RES analgesic properties have been demonstrated, although the bases of these mechanisms have not been fully elucidated. The aim of this study was to evaluate the involvement of opioid and cannabinoid systems in RES-induced peripheral antinociception. Paw withdrawal method was used and hyperalgesia was induced by carrageenan (200 µg/paw). All drugs were given by intraplantar injection in male Swiss mice (n = 5). RES (100 µg/paw) administered in the right hind paw induced local antinociception that was antagonized by naloxone, non-selective opioid receptor antagonist, and clocinnamox, µOR selective antagonist. Naltrindole and nor-binaltorfimine, selective antagonists for δOR and kOR, respectively, did not reverse RES-induced peripheral antinociception. CB1R antagonist AM251, but not CB2R antagonist AM630, antagonized RES-induced peripheral antinociception. Peripheral antinociception of RES intermediate-dose (50 µg/paw) was increased by: (i) bestatin, inhibitor of endogenous opioid degradation involved-enzymes; (ii) MAFP, inhibitor of anandamide amidase; (iii) JZL184, inhibitor of 2-arachidonoylglycerol degradation involved-enzyme; (iv) VDM11, endocannabinoid reuptake inhibitor. Acute and peripheral administration of RES failed to affect the amount of µOR, CB1R and CB2R. Experimental data suggest that RES induces peripheral antinociception through µOR and CB1R activation by endogenous opioid and endocannabinoid releasing.

Role of Endocannabinoid System in the Peripheral Antinociceptive Action of Aripiprazole.

BACKGROUND: Recently, we demonstrated that the antipsychotic dopaminergic and serotoninergic agonist aripiprazole induced peripheral antinociception. However, the mechanism underlying this effect has not been fully established. Here, our aim was to identify possible relationships between this action of aripiprazole and the endocannabinoid system. METHODS: All drugs were given locally into the right hind paw of male Swiss mice weighing 30-35 g in a volume of 20 µL. The hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2 µg). Aripiprazole was injected 10 minutes before the measurement, and an irreversible inhibitor of anandamide hydrolase (MAFP), an inhibitor for monoacylglycerol lipase (JZL184), and an anandamide reuptake inhibitor (VDM11) were given 10 minutes before the aripiprazole. Nociceptive thresholds were measured using an algesimetric apparatus in the third hour after prostaglandin E2 injection. Data were analyzed by ANOVA and Bonferroni tests. RESULTS: The antinociceptive effect induced by aripiprazole (100 µg) was blocked by cannabinoid 1 or 2 receptor antagonists AM251 (40 µg [P < .01], 80 µg [P < .0001], and 160 µg [P < .0001]) and AM630 (100 µg [P < .0001], 200 µg [P < .0001], and 400 µg [P < .0001]), respectively. The peripheral antinociception induced by aripiprazole (25 µg) was enhanced by administration of the inhibitor of fatty acid amide hydrolase (MAFP, 0.5 µg [P < .0001]) or monoacylglycerol lipase (JZL184, 4 µg [P < .0001]). Moreover, a similar enhancement was observed with the anandamide reuptake inhibitor (VDM11, 2.5 µg [P < .0001]). CONCLUSIONS: These results provide evidence for the involvement of the endocannabinoid system in peripheral antinociception induced by aripiprazole treatment.

Anti-inflammatory and antinociceptive properties of the hydroalcoholic fractions from the leaves of Annona crassiflora Mart. in mice.

BACKGROUND: Annona crassiflora Mart., popularly known as "Araticum", is a native tree of the Brazilian Cerrado used in folk medicine for treatment of pain and inflammatory diseases. We proposed to analyze analgesic and anti-inflammatory properties of the filtrate (F1) and the precipitate (F2) of the hydroalcoholic fraction from the leaves of Annona crassiflora Mart. in mice. MATERIALS AND METHODS: Swiss mice were submitted to formalin-induced nociception test and tail-flick reflex test, to assess antinociceptive properties, and to the rota-rod test, for motor performance analyses. To evaluate anti-inflammatory properties, F1 and F2 were orally administered 1 h prior to the intrathoracic injection of carrageenan, zymosan, LPS, CXCL8, or vehicle in Balb/c mice and neutrophil infiltration was evaluated 4 h after injection. RESULTS: F1 and F2 reduced the licking time in the second phase of formalin-induced nociception test, but only F2 showed a dose-dependent response. Neither F1 nor F2 reduced the latency time in the tail-flick reflex test. In addition, motor performance alteration was not observed in F1- or F2-treated mice. F2 treatment significantly inhibited the neutrophilia induced by carrageenan, LPS, or CXCL8, but not zymosan. CONCLUSIONS: The experimental data demonstrated that hydroalcoholic fractions of Annona crassiflora Mart. leaves have remarkable anti-inflammatory and antinociceptive activities.

Peltatoside Isolated from Annona crassiflora Induces Peripheral Antinociception by Activation of the Cannabinoid System.

Peltatoside is a natural compound isolated from leaves of Annona crassiflora Mart., a plant widely used in folk medicine. This substance is an analogue of quercetin, a flavonoid extensively studied because of its diverse biological activities, including analgesic effects. Besides, a previous study suggested, by computer structure analyses, a possible quercetin-CB1 cannabinoid receptor interaction. Thus, the aim of this work was to assess the antinociceptive effect of peltatoside and analyze the cannabinoid system involvement in this action. The mouse paw pressure test was used and hyperalgesia was induced by intraplantar injection of carrageenan (200 µg/paw). All used drugs were administered by intraplantar administration in Swiss male mice (n = 6). Peltatoside (100 µg/paw) elicited a local inhibition of hyperalgesia. The peripheral antinociceptive action of peltatoside was antagonized by the CB1 cannabinoid antagonist AM251 (160 µg/paw), but not by CB2 cannabinoid antagonist AM630 (100 µg/paw). In order to assess the role of endocannabinoids in this peripheral antinociceptive effect, we used (i) [5Z,8Z,11Z,14Z]-5,8,11,14-eicosatetraenyl-methyl ester phosphonofluoridic acid, an inhibitor of anandamide amidase; (ii) JZL184, an inhibitor for monoacylglycerol lipase, the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol; and (iii) VDM11, an endocannabinoid reuptake inhibitor. MAFP, JZL184, and VDM11 did not induce antinociception, respectively, at the doses 0.5, 3.8, and 2.5 µg/paw, however, these three drugs were able to potentiate the peripheral antinociceptive effect of peltatoside at an intermediary dose (50 µg/paw). Our results suggest that this natural substance is capable of inducing analgesia through the activation of peripheral CB1 receptors, involving endocannabinoids in this process.

Natural Diterpenes from Coffee, Cafestol, and Kahweol Induce Peripheral Antinoceception by Adrenergic System Interaction.

Cafestol and kahweol are diterpenes found only in the non-saponified lipid fraction of coffee. They are released during boiling and retained in the filtration process. Previous studies have shown peripheral antinociception induced by endogenous opioid peptides released by these diterpenes. Considering that the activation of the opioid system leads to a noradrenaline release, the aim of this study was to verify the participation of the noradrenergic system in the peripheral antinociception induced by cafestol and kahweol. Hyperalgesia was induced by an intraplantar injection of prostaglandin E2 (2 µg). Cafestol or kahweol (80 µg/paw) were administered locally into the right hindpaw alone, and after the agents α 2-adrenoceptor antagonist yohimbine (5, 10 and 20 µg/paw), α 2 A-adrenoceptor antagonist BRL 44 408 (40 µg/paw), α 2B-adrenoceptor antagonist imiloxan (40 µg/paw), α 2 C-adrenoceptor antagonist rauwolscine (10, 15 and 20 µg/paw), α 2D-adrenoceptor antagonist RX 821 002 (40 µg/paw), α 1-adrenoceptor antagonist prazosin (0.5, 1 and 2 µg/paw), or ß-adrenoceptor antagonist propranolol (150, 300 and 600 ng/paw), respectively. Noradrenaline reuptake inhibitor reboxetine (30 µg/paw) was administered prior to cafestol or kahweol low dose (40 µg/paw) and guanetidine 3 days prior to the experiment (30 mg/kg, once a day), depleting the noradrenaline storage. Intraplantar injection of cafestol or kahweol (80 µg/paw) induced a peripheral antinociception against hyperalgesia induced by PGE2. This effect was reversed by intraplantar injections of yohimbine, rauwolscine, prazosin and propranolol. Reboxetine injection intensified the antinociceptive effect of cafestol or kahweol low-dose, and guanethidine reversed almost 70 % of the cafestol or kahweol-induced peripheral antinociception. This study gives evidence that the noradrenergic system participates in cafestol and kahweol-induced peripheral antinociception with the release of endogenous noradrenaline.

The Nitric oxide/CGMP/KATP pathway mediates systemic and central antinociception induced by resistance exercise in rats.

Resistance exercise (RE) is characterized to increase strength, tone, mass, and/or muscular endurance and also for produces many beneficial effects, such as blood pressure and osteoporosis reduction, diabetes mellitus control, and analgesia. However, few studies have investigated endogenous mechanisms involved in the RE-induced analgesia. Thus, the aim of this study was evaluate the role of the NO/CGMP/KATP pathway in the antinociception induced by RE. Wistar rats were submitted to acute RE in a weight-lifting model. The nociceptive threshold was measured by mechanical nociceptive test (paw-withdrawal). To investigate the involvement of the NO/CGMP/KATP pathway the following nitric oxide synthase (NOS) non-specific and specific inhibitors were used: N-nitro-l-arginine (NOArg), Aminoguanidine, N5-(1-Iminoethyl)-l-ornithine dihydrocloride (l-NIO), Nω-Propyl-l-arginine (l-NPA); guanylyl cyclase inhibitor, 1H-[1,2,4]oxidiazolo[4,3-a]quinoxalin-1-one (ODQ); and KATP channel blocker, Glybenclamide; all administered subcutaneously, intrathecally and intracerebroventricularly. Plasma and cerebrospinal fluid (CSF) nitrite levels were determined by spectrophotometry. The RE protocol produced antinociception, which was significantly reversed by NOS specific and unspecific inhibitors, guanylyl cyclase inhibitor (ODQ) and KATP channel blocker (Glybenclamide). RE was also responsible for increasing nitrite levels in both plasma and CSF. These finding suggest that the NO/CGMP/KATP pathway participates in antinociception induced by RE.

Ang-(1-7) activates the NO/cGMP and ATP-sensitive K+ channels pathway to induce peripheral antinociception in rats.

Angiotensin-(1-7) is a bioactive component of the renin-angiotensin system that is formed endogenously and induces nitric oxide release in several tissues. The L-arginine/NO/cyclic GMP pathway and ATP-sensitive K+ channels have been proposed as the mechanism of action for the peripheral antinociception of several groups of drug and endogenous substances, including opioids, non-steroidal analgesics, acetylcholine and others. The aim of the present study was to investigate the involvement of the L-arginine/NO/cGMP and KATP+ pathway on antinociception induced by angiotensin-(1-7). Paw pressure in rats was used to induce hyperalgesia via an intraplantar injection of prostaglandin E2 (2 µg/paw). Ang-(1-7) (2, 3 and 4 µg/paw) elicited a local peripheral antinociceptive effect that was antagonized by the nonselective NO synthase (NOS) inhibitor L-NOarg and the selective neuronal NOS (nNOS) inhibitor L-NPA. The selective inhibition of endothelial (eNOS) and inducible (iNOS) NOS by L-NIO and L-NIL, respectively, was ineffective at blocking the effects of a local Ang-(1-7) injection. In addition, the level of nitrite in the homogenized paw tissue, as determined by a colorimetric assay, indicated that exogenous Ang-(1-7) is able to induce NO release. The soluble guanylyl cyclase inhibitor ODQ and the specific blocker of ATP-sensitive K+ channels glibenclamide (40, 80 and 160 µg/paw) antagonized the Ang-(1-7) response. The results provide evidence that Ang-(1-7) most likely induces peripheral antinociceptive effects via the L-arginine/NO/cGMP pathway and KATP+ pathway activation.

Acute resistance exercise induces antinociception by activation of the endocannabinoid system in rats.

BACKGROUND: Resistance exercise (RE) is also known as strength training, and it is performed to increase the strength and mass of muscles, bone strength, and metabolism. RE has been increasingly prescribed for pain relief. However, the endogenous mechanisms underlying this antinociceptive effect are still largely unexplored. Thus, we investigated the involvement of the endocannabinoid system in RE-induced antinociception. METHODS: Male Wistar rats were submitted to acute RE in a weight-lifting model. The nociceptive threshold was measured by a mechanical nociceptive test (paw pressure) before and after exercise. To investigate the involvement of cannabinoid receptors and endocannabinoids in RE-induced antinociception, cannabinoid receptor inverse agonists, endocannabinoid metabolizing enzyme inhibitors, and an anandamide reuptake inhibitor were injected before RE. After RE, CB1 cannabinoid receptors were quantified in rat brain tissue by Western blot and immunofluorescence. In addition, endocannabinoid plasma levels were measured by isotope dilution-liquid chromatography mass spectrometry. RESULTS: RE-induced antinociception was prevented by preinjection with CB1 and CB2 cannabinoid receptor inverse agonists. By contrast, preadministration of metabolizing enzyme inhibitors and the anandamide reuptake inhibitor prolonged and enhanced this effect. RE also produced an increase in the expression and activation of CB1 cannabinoid receptors in rat brain tissue and in the dorsolateral and ventrolateral periaqueductal regions and an increase in endocannabinoid plasma levels. CONCLUSIONS: The present study suggests that a single session of RE activates the endocannabinoid system to induce antinociception.

Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to opioidergic activation.

Plants belonging to the genus Maytenus are routinely used in folk medicine for the treatment of pain diseases. Our previous phytochemical study of the roots of Maytenus imbricata resulted in the isolation and characterization of tingenone, a pentacyclic triterpene. Natural triterpenoids are of growing interest because they have several biological activities, including analgesic properties. The present study assessed the involvement of the opiodergic pathway in the tingenone-induced antinociceptive effect against hyperalgesia induced by prostaglandin E2 (2 µg) in the peripheral pathway. We evaluated the effect of several antagonists to opioid receptors using the mouse paw pressure test. Tingenone administered into the right hind paw induced a local antinociceptive effect that was antagonized by naloxone, a nonselective antagonist to opioid receptors. Clocinnamox, naltrindole, and nor-binaltorphimine are selective antagonists to µ, δ, and κ receptors, respectively, which reverted the peripheral antinociception induced by tingenone. Bestatine acts as an inhibitor of aminopeptidase, an enzyme that degrades endogenous opioid peptides, and was shown to intensify the antinociceptive effect of tingenone. The results suggest that the opioidergic system participates in the peripheral antinociception induced by tingenone.

Effect of dietary caloric restriction on the nociceptive threshold of rats that underwent aerobic and resistance exercise training.

The purpose of this study was to evaluate the effect that exercise and caloric restriction have on the nociceptive threshold of rats. Male Wistar rats were divided into two groups: one group that was fed ad libitum (FED) and another group that was subjected to dietary caloric restriction (CR). The CR group received 50% of the food the FED group received, for 4 weeks. Both groups were submitted to aerobic (AE) and resistance (RE) exercise training protocols performed in a rodent treadmill and in a weight-lifting exercise model, respectively. Mechanical and thermal nociceptive thresholds were measured by tail-flick and paw-withdrawal tests, respectively. Both exercise protocols produced antinociception, but there was no difference found between the FED and CR groups after either 1 or 4 weeks. Additionally, although dietary caloric restriction alone did not result in antinociception, it did increase the running time of animals during aerobic exercise and increased the load lifted in resistance exercise after 4 weeks. These results indicate that caloric restriction for 1 or 4 weeks did not alter the nociceptive threshold, but could play an important role in improvement of physical performance.

Opioid receptors are not involved in the increase of the nociceptive threshold induced by aerobic exercise.

OBJECTIVE: To investigate the involvement of opioid receptors in antinociception induced by different aerobic exercise protocols in rats. METHODS: This experimental study, conducted in the Federal University of Minas Gerais, Belo Horizonte, Brazil from November 2011 to May 2012, included 60 female Wistar rats, divided into 10 groups of 6 animals per group. The rats were subjected to different aerobic exercise protocols: acute, cardiac stress, eccentric, and training. The nociceptive threshold was measured by the paw-withdrawal test. To investigate the involvement of the endogenous opioids system, the non-selective opioid receptor antagonist naloxone (5 mg/kg) was administered subcutaneously before the beginning of the exercise. RESULTS: All exercise protocols increased the nociceptive threshold for 15 minutes. The naloxone pre-treatment did not alter the antinociception induced by aerobic exercise protocols. CONCLUSION: The endogenous opioids system did not participate in the antinociceptive effect produced by the aerobic exercise protocols.

Symbiosis: Aquatic apicomplexans shedding light on disguised associations.

Aquatic apicomplexans called Corallicolida have been found in tropical and coral-reef settings, infecting many coral species. New data challenge this tropical distribution and expand the corallicolids' range well into the cold temperate. Surprisingly, the sister clade to corallicolids infects only one group of vertebrates - bony fishes.

Exploring Diagnostic Performance of a Screening Instrument for ADHD and DSM-5 Number of Symptoms Criterion in Primary School Students From Mozambique.

OBJECTIVE: To explore the ADHD diagnostic performance of a screening instrument, and which DSM-5 ADHD number of symptoms (criterion A) was best associated with impairment in a sample of students from 106 primary schools in Nampula, Mozambique. METHODS: A random sample of 748 students were assessed using SNAP-IV and 152 youths (76 positive and 76 negative screeners) were invited for psychiatric diagnostic confirmation. RESULTS: The performance of the screening instrument for predicting ADHD diagnosis was poor (all AUCs < 0.53). No other cut-off worked best in predicting impairment than the six symptoms cutoff suggested by DSM-5 for both inattention (AUC = 0.78; 95% CI [0.69, 0.86]) and hyperactivity/impulsivity (AUC = 0.75; 95% CI [0.67, 0.84]). CONCLUSION: Our findings highlight the adequacy of the DSM-5 ADHD criterion A in an African culture but indicate low diagnostic performance of a screening instruments only based in parent or teacher reports on symptoms to predict ADHD diagnosis.

Study on peripheral antinociception induced by hydrogen peroxide (H2O2): characterization and mechanisms.

The present study aimed to evaluate the possible peripheral H2O2-induced antinociception and determine the involvement of opioidergic, cannabinoidergic and nitrergic systems, besides potassium channels in its antinociceptive effect. Prostaglandin E2 was used to induce hyperalgesia in male Swiss mice using the mechanical paw pressure test. H2O2 (0.1, 0.2, 0.3 µg/paw) promoted a dose-dependent antinociceptive effect that was not observed in contralateral paw. Female mice also showed antinociception in the model. The partial H2O2-induced antinociception was potentiated by the inhibitor of catalase enzyme, aminotriazole (40, 60, 80 µg/paw). The antinociception was not reversed by opioid and cannabinoid receptor antagonists naloxone, AM 251 and AM 630. The involvement of nitric oxide (NO) was observed by the reversal of H2O2-induced antinociception using the non-selective inhibitor of nitric oxide synthases L-NOarg and by inhibition of iNOS (L-NIL), eNOS (L-NIO) and nNOS (L-NPA). ODQ, a cGMP-forming enzyme selective inhibitor, also reversed the antinociception. The blockers of potassium channels voltage-gated (TEA), ATP-sensitive (glibenclamide), large (paxillin) and small (dequalinium) conductance calcium-activated were able to revert H2O2 antinociception. Our data suggest that H2O2 induced a peripheral antinociception in mice and the NO pathway and potassium channels (voltage-gated, ATP-sensitive, calcium-activated) are involved in this mechanism. However, the role of the opioid and cannabinoid systems was not evidenced.