RESUMO

BACKGROUND: The development of analgesic and anti-inflammatory drugs plays a crucial role in modern medicine, aiming to alleviate pain and reduce inflammation in patients. Opioids and nonsteroidal anti-inflammatory drugs are groups of drugs conventionally used to treat pain and inflammation, but a wide range of adverse effects and ineffectiveness in some pathological conditions leads us to search for new drugs with analgesic and anti-inflammatory properties. OBJECTIVES: In this regard, the authors intend to investigate the ((2s,6s)-6-ethyl-tetrahydro-2h-pyran- 2-yl) methanol compound (LS20) on pain and acute inflammation. METHODS: Male Swiss mice were evaluated using acetic acid-induced abdominal writhing, formalin, and tail-flick as models of nociceptive evaluation and edema paw, air pouch and cell culture as models of inflammatory evaluation besides the rotarod test for assessment of motor impairment. RESULTS: The compound showed an effect on the acetic acid-induced abdominal writhing, formalin and tail-flick tests. Studying the mechanism of action, reversion of the antinociceptive effect of the compound was observed from previous intraperitoneal administration of selective and non-selective opioid antagonists on the tail flick test. In addition, the compound induced an antiedematogenic effect and reduced leukocyte migration and the production of pro-inflammatory cytokines in the air pouch model. LS20 was able to maintain cell viability, in addition to reducing cell production of TNF-α and IL-6. CONCLUSION: In summary, the LS20 compound presented an antinociceptive effect, demonstrating the participation of the opioid system and an anti-inflammatory effect related to the inhibition of pro-inflammatory cytokine production. The compound also demonstrated safety at the cellular level.

Assuntos

Analgésicos , Anti-Inflamatórios , Dor , Piranos , Animais , Masculino , Camundongos , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Piranos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Dor/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Metanol/química , Ácido Acético , Edema/tratamento farmacológico , Edema/induzido quimicamente , Citocinas/metabolismo

RESUMO

Popular medicine has been using oleoresin from several species of copaíba tree for the treatment of various diseases and its clinical administration potentially causes antinociception. Electrical stimulation of ventrolateral (vlPAG) and dorsolateral (dlPAG) columns of the periaqueductal gray matter also causes antinociception. The aim this study was to verify the antinociceptive effect of oleoresin extracted from Copaifera langsdorffii tree and to test the hypothesis that oleoresin-induced antinociception is mediated by µ1- and κ-opioid receptors in the vlPAG and dlPAG. Nociceptive thresholds were determined by the tail-flick test in Wistar rats. The copaíba tree oleoresin was administered at different doses (50, 100 and 200 mg/kg) through the gavage technique. After the specification of the most effective dose of copaíba tree oleoresin (200 mg/kg), rats were pretreated with either the µ1-opioid receptor selective antagonist naloxonazine (at 0.05, 0.5 and 5 µg/ 0.2 µl in vlPAG, and 5 µg/ 0.2 µl in dlPAG) or the κ-opioid receptor selective antagonist nor-binaltorphimine (at 1, 3 and 9 nmol/ 0.2 µl in vlPAG, and 9 nmol/ 0.2 µl in dlPAG). The blockade of µ1 and κ opioid receptors of vlPAG decreased the antinociception produced by copaíba tree oleoresin. However, the blockade of these receptors in dlPAG did not alter copaíba tree oleoresin-induced antinociception. These data suggest that vlPAG µ1 and κ opioid receptors are critically recruited in the antinociceptive effect produced by oleoresin extracted from Copaifera langsdorffii.

Assuntos

Substância Cinzenta Periaquedutal , Extratos Vegetais , Receptores Opioides kappa , Ratos , Animais , Ratos Wistar , Árvores , Antagonistas de Entorpecentes/farmacologia , Analgésicos/farmacologia , Receptores Opioides mu

RESUMO

The rostral ventromedial medulla (RVM) is a brainstem structure critical for the descending pain modulation system involved in both pain facilitation and inhibition through its projection to the spinal cord. Since the RVM is well connected with pain- and stress-engaged brain structures, such as the anterior cingulate cortex, nucleus accumbens, and amygdala, its involvement in stress responses has become a matter of great interest. While chronic stress has been proposed as a trigger of pain chronification and related psychiatric comorbidities due to maladaptive stress responses, acute stress triggers analgesia and other adaptative responses. Here we reviewed and highlighted the critical role of the RVM in stress responses, mainly in acute stress-induced analgesia (SIA) and chronic stress-induced hyperalgesia (SIH), providing insights into pain chronification processes and comorbidity between chronic pain and psychiatric disorders.

RESUMO

Background: Naltrexone has been approved for alcohol and opioid abuse by the FDA. At low-dose naltrexone (LDN) has been used in several diseases including chronic pain and autoimmune conditions, including rheumatic disorders. Aim: To review the use of LDN in rheumatic diseases: systemic sclerosis (SSc), dermatomyositis (DM), Sjögren's syndrome (SS), rheumatoid arthritis (RA), and fibromyalgia (FM). Methods: PubMed and Embase databases were searched for articles on LDN and rheumatic diseases between 1966 and August 2022. Results: Seven studies in FM have been identified: in this disease LDN has showed beneficial effects on pain and well-being. In SS, two articles with 3 cases description showed that LDN may be of help in the pain treatment. LDN relieved pruritus in scleroderma (a case description with a series of 3 patients) and dermatomyositis (description of 3 patients in two articles). In RA a study using Norwegian Prescription Database showed that LDN was associated to reduction in the use of analgesic and DMARDs. No serious side effects were detected. Conclusion: This review shows that LDN is a promising and safe therapy to be used in some rheumatic disease. However, the data is limited and needs to be reproduced in larger studies.

RESUMO

Opioid receptors mediate antinociceptive effects. Methanolic fractions from sugarcane varieties (MFSCf) were evaluated in classic nociception models. Interactions between bioactive compounds and the µ-opioid receptor (µOR) through docking analysis were also studied. Five methanolic fractions of sugarcane juice were obtained and analysed by LC-ESI-MS/MS. The fractions and standards of phenolic compounds were evaluated in a nociception model using the formalin test. All MFSCfs exhibited antinociceptive activity in the first phase of the formalin test. Docking analyses corroborates with the in vivo test results, suggesting that the phenolic substances are able to activate µOR. These results, for the first time, implicate phenolic constituents from sugarcane juice and other phenolic compounds in the activation of µOR. The antinociceptive activity of fractions from sugarcane juice suggests the potential pharmacological use of this species, widely cultivated in Brazil.

Assuntos

Flavonoides , Saccharum , Flavonoides/farmacologia , Simulação de Acoplamento Molecular , Receptores Opioides , Espectrometria de Massas em Tandem , Analgésicos/farmacologia , Fenóis/farmacologia , Metanol

RESUMO

Pain is responsible for inducing physical and mental stress, interfering negatively in patients' quality of life. Classic analgesic drugs, such as opioids and non-steroidal anti-inflammatory drugs, are known for their wide range of adverse effects, making it important to develop new drugs. Thus, this study aimed to analyse the action of the hybrid compound cis- (±) -acetate of 4-chloro-6- (naphthalene-1-yl) -tetrahydro-2h-pyran -2-yl) methyl2- (2- [2,6-dichlorophenylamine] phenyl (LS19) under acute nociceptive conditions, and deepened the understanding of the responsible mechanisms. Male Swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail flick, capsaicin- and glutamate-induced nociception, thermal stimulation in animals injected with capsaicin and rotarod tests besides the acute and subchronic toxicological evaluation. The compound showed effect on the acetic acid-induced abdominal writhing, formalin (both phases), tail flick, thermal stimulation in animals injected with capsaicin and capsaicin-induced nociception tests. In the study of the mechanism of action was observed reversion of the antihyperalgesic effect of the compound from the previous intraperitoneal and intrathecal administration of naloxone, nor-binaltorphimine, naltrindole, methylnaltrexone, 7-nitroindazole, L-NAME, ODQ, glibenclamide on the tail flick test. In the thermal stimulation in animals injected with capsaicin, the compound showed antinociceptive effect by oral and intraplantar routes, besides to reducing the levels of TNF-α, IL-1ß and PGE2 in the paws previously administered with capsaicin. There were no signs of acute and subchronic intoxication with the compound. In summary, the compound LS19 presented spinal and local antihyperalgesic effect, demonstrating participation of the opioid/NO/cGMP/K+ ATP pathway and TRPV1 receptors and it demonstrated safety in its use in mice.

Assuntos

Anti-Inflamatórios não Esteroides , Dor , Piranos , Animais , Humanos , Masculino , Camundongos , Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Capsaicina/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/toxicidade , Temperatura Alta/efeitos adversos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Piranos/química , Piranos/farmacologia

RESUMO

Spirulina platensis is a "super-food" and has attracted researchers' attention due to its anti-inflammatory, antioxidant, and analgesic properties. Herein, we investigated the antinociceptive effects of Spirulina in different rodent behavior models of inflammatory pain. Male Swiss mice were treated with Spirulina (3-300 mg/kg, p.o.), indomethacin (10 mg/kg, p.o.), or vehicle (0.9% NaCl 10 mL/kg). Behavioral tests were performed with administration of acetic acid (0.6%, i.p.), formalin 2.7% (formaldehyde 1%, i.pl.), menthol (1.2 µmol/paw, i.pl.), cinnamaldehyde (10 nmol/paw, i.pl.), capsaicin (1.6 µg/paw, i.pl.), glutamate (20 µmol/paw, i.pl.), or naloxone (1 mg/kg, i.p.). The animals were also exposed to the rotarod and open field test to determine possible effects of Spirulina on locomotion and motor coordination. The quantitative phytochemical assays exhibited that Spirulina contains significant concentrations of total phenols and flavonoid contents, as well as it showed a powerful antioxidant effect with the highest scavenging activity. Oral administration of Spirulina completely inhibited the abdominal contortions induced by acetic acid (ED50 = 20.51 mg/kg). Spirulina treatment showed significant inhibition of formalin-induced nociceptive behavior during the inflammatory phase, and the opioid-selective antagonist markedly blocked this effect. Furthermore, our data indicate that the mechanisms underlying Spirulina analgesia appear to be related to its ability to modulate TRMP8 and TRPA1, but not by TRPV1 or glutamatergic system. Spirulina represents an orally active and safe natural analgesic that exhibits great therapeutic potential for managing inflammatory pain disorders.

Assuntos

Analgésicos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor Nociceptiva/tratamento farmacológico , Extratos Vegetais/farmacologia , Spirulina/química , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPM/metabolismo , Analgésicos/uso terapêutico , Animais , Capsaicina/farmacologia , Masculino , Camundongos , Naloxona/farmacologia , Nociceptividade/efeitos dos fármacos , Extratos Vegetais/uso terapêutico

RESUMO

Tissue injury results in the release of inflammatory mediators, including a cascade of nociceptive substances, which contribute to development of hyperalgesia. In addition, during this process endogenous analgesic substances are also peripherally released with the aim of controlling the hyperalgesia. Thus, 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 opioid system. Thus, male Swiss mice and the paw withdrawal test were used. All substances were injected by the intraplantar route. Carrageenan, TNF-α, CXCL-1, IL1-ß, NE and PGE2 induced hyperalgesia. Selectives µ (clocinamox), δ (naltrindole) and κ (norbinaltorphimine, nor-BNI) and non-selective (naloxone) opioid receptor antagonists potentiated the hyperalgesia induced by carrageenan, TNF-α, CXCL-1 and IL1-ß. In contrast, when the enzyme N-aminopeptidase involved in the degradation of endogenous opioid peptides was inhibited by bestatin, the hyperalgesia was significantly reduced. In addition, the western blotting assay indicated that the expression of the opioid δ receptor was increased after intraplantar injection of carrageenan. The data obtained in this work corroborate the hypothesis that TNF-α, CXCL-1 and IL-ß cause, in addition to hyperalgesia, the release of endogenous substances such as opioid peptides, which in turn exert endogenous control over peripheral inflammatory pain.

Assuntos

Quimiocina CXCL1 , Hiperalgesia/induzido quimicamente , Interleucina-1beta , Nociceptividade , Dor Nociceptiva/induzido quimicamente , Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Fator de Necrose Tumoral alfa , Animais , Carragenina , Dinoprostona , Modelos Animais de Doenças , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Masculino , Camundongos , Antagonistas de Entorpecentes/farmacologia , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Dor Nociceptiva/prevenção & controle , Norepinefrina , Receptores Opioides/efeitos dos fármacos , Transdução de Sinais

RESUMO

BACKGROUND: A. gratissima is a shrub used in folk medicine as analgesic and sedative. However, studies on its antinociceptive activity are scarce. This research aimed to evaluate the antinociceptive effect of a supercritical carbon dioxide (SCCO2) extract of A. gratissima leaves (EAG) in mice. METHODS: A. gratissima leaves were subjected to extraction with supercritical CO2 (60 °C, 200 bar). The chemical composition of EAG was determined by gas chromatography-mass spectrometry (GC-MS). The antinociceptive profile of the extract (1, 10 and 30 mg/kg, p.o.) was established using acetic acid-induced abdominal contraction tests and formalin-induced paw-licking tests. The open field and rota-rod tests were used to evaluate a possible interference of EAG on mice motor performance. The contribution of the opioid system and adenosine triphosphate (ATP) sensitive K+ channels in the mechanism(s) of EAG action was evaluated by specific receptor blockers. EAG's acute toxicity was investigated using OECD 423 guideline. RESULTS: The GC-MS revealed the presence of sesquiterpenes (guaiol and pinocamphone) in the EAG. Doses of 10 mg/kg and 30 mg/kg significantly reduced the number of abdominal writhes and paw licking time in mice in the formalin test. The EAG did not affect the locomotor activity and motor coordination of the mice. The antinociceptive effect of the EAG was prevented by glibenclamide in the mice formalin test, unlike naloxone pre-treatment. The acute administration of EAG caused no mortality. CONCLUSION: A. gratissima leaves possess antinociceptive effect, mediated by K+ channels sensitive to ATP.

Assuntos

Analgésicos , Extratos Vegetais , Verbenaceae , Analgésicos/farmacologia , Animais , Dióxido de Carbono , Canais KATP/metabolismo , Camundongos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Verbenaceae/química

RESUMO

Animal venoms are an almost inexhaustible source for promising molecules with biological activity and the venom of Phoneutria nigriventer spider is a good example of this. Among several other toxins obtained from this venom, PnTx4(6-1), also called δ-Ctenitoxin-Pn1a, was isolated and initially described as an insect toxin that binds to the site 3 of sodium channels in cockroach nerve cord synaptosomes (Periplaneta americana) and slows down sodium current inactivation in isolated axons of this animal. This toxin did not cause any apparent toxicity to mice when intracerebroventricularly injected (30 µg). Subsequently, it was demonstrated that PnTx4(6-1) has an antinociceptive effect in three different pain models: inflammatory, induced by carrageenan; nociceptive, induced by prostaglandin E2 and neuropathic, induced by sciatic nerve constriction. Using diverse antagonists from receptors, it was shown that the cannabinoid system, via the CB1 receptor, and the opioid system, through the µ and δ receptors, are both involved in the antinociceptive effect of PnTx4(6-1). In the present work, it was synthesized a peptide, named PnAn13, based on the amino acid sequence of PnTx4(6-1) in order to try to reproduce or increase the analgesic effect of the toxin. As it was seen for the toxin, PnAn13 had antinociceptive activity, when intrathecally injected, and this effect involved the cannabinoid and opioid systems. In addition, when it was evaluated the peripheral effect of PnAn13, via intraplantar administration, this peptide was able to reverse the hyperalgesic threshold, evoked by prostaglandin E2. Therefore, using different pharmacological tools, it was shown the participation of cannabinoid and opioid systems in this effect.

RESUMO

The anatomo-physiological disruptions inherent to different categories of the Fetal Alcohol Spectrum Disorder do not encompass all the negative consequences derived from intrauterine ethanol (EtOH) exposure. Preclinical, clinical and epidemiological studies show that prenatal EtOH exposure also results in early programming of alcohol affinity. This affinity has been addressed through the examination of how EtOH prenatally exposed organisms recognize and prefer the drug's chemosensory cues and their predisposition to exhibit heightened voluntary EtOH intake during infancy and adolescence. In altricial species these processes are determined by the interaction of at least three factors during stages equivalent to the 2nd and 3rd human gestational trimester: (i) fetal processing of the drug's olfactory and gustatory attributes present in the prenatal milieu; (ii) EtOH's recruitment of central reinforcing effects that also imply progressive sensitization to the drug's motivational properties; and (iii) an associative learning process involving the prior two factors. This Pavlovian learning phenomenon is dependent upon the recruitment of the opioid system and studies also indicate a significant role of EtOH's principal metabolite (acetaldehyde, ACD) which is rapidly generated in the brain via the catalase system. The central and rapid accumulation of this metabolite represents a major factor involved in the process of fetal alcohol programming. According to recent investigations, it appears that ACD exerts early positive reinforcing consequences and antianxiety effects (negative reinforcement). Finally, this review also acknowledges human clinical and epidemiological studies indicating that moderate and binge-like drinking episodes during gestation result in neonatal recognition of EtOH's chemosensory properties coupled with a preference towards these cues. As a whole, the studies under discussion emphasize the notion that even subteratogenic EtOH exposure during fetal life seizes early functional sensory and learning capabilities that pathologically shape subsequent physiological and behavioral reactivity towards the drug.

RESUMO

Lavandula angustifolia (LaEO) essential oil has been widely used by aromatherapy in the treatment of various clinical conditions, with evidence of its analgesic and anti-inflammatory potential. Our results demonstrate that sixty-five substances were identified in LaEO. Among the compounds found, the major ones were linalool (30.61%) and linalyl acetate (20.36%). We found that LaEO inhalation reduces mechanical hyperalgesia in conditions of chronic inflammatory and neuropathic pain. Furthermore, this effect seems to be mediated by peripheral and central opioid and cannabinoid 2 receptors. The findings of the present study suggests that the LaEO inhalation is effective on the chronic pain treatment.

Assuntos

Hiperalgesia , Óleos Voláteis/farmacologia , Receptores de Canabinoides/metabolismo , Receptores Opioides/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Hiperalgesia/metabolismo , Inflamação/metabolismo , Lavandula , Camundongos , Neuralgia/metabolismo , Extratos Vegetais/farmacologia

RESUMO

AIM: To compare the effect of 150 min vs. 300 min of weekly moderate intensity exercise training on the activation of the opioid system and apoptosis in the hearts of a diet-induced obesity model. METHODS: Male Wistar rats were fed with either control (CON) or high fat (HF) diet for 32 weeks. At the 20th week, HF group was subdivided into sedentary, low (LEV, 150 min·week-1) or high (HEV, 300 min·week-1) exercise volume. After 12 weeks of exercise, body mass gain, adiposity index, systolic blood pressure, cardiac morphometry, apoptosis biomarkers and opioid system expression were evaluated. RESULTS: Sedentary animals fed with HF presented pathological cardiac hypertrophy and higher body mass gain, systolic blood pressure and adiposity index than control group. Both exercise volumes induced physiological cardiac hypertrophy, restored systolic blood pressure and improved adiposity index, but only 300 min·week-1 reduced body mass gain. HF group exhibited lower proenkephalin, PI3K, ERK and GSK-3ß expression, and greater activated caspase-3 expression than control group. Compared to HF, no changes in the cardiac opioid system were observed in the 150 min·week-1 of exercise training, while 300 min·week-1 showed greater proenkephalin, DOR, KOR, MOR, Akt, ERK and GSK-3ß expression, and lower activated caspase-3 expression. CONCLUSION: 300 min·week-1 of exercise training triggered opioid system activation and provided greater cardioprotection against obesity than 150 min·week-1. Our findings provide translational aspect with clinical relevance about the critical dose of exercise training necessary to reduce cardiovascular risk factors caused by obesity.

Assuntos

Cardiomegalia/metabolismo , Condicionamento Físico Animal/fisiologia , Receptores Opioides/fisiologia , Adiposidade , Animais , Apoptose/fisiologia , Pressão Sanguínea , Peso Corporal , Dieta Hiperlipídica , Encefalinas/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Coração/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Obesidade/metabolismo , Obesidade/fisiopatologia , Fosfatidilinositol 3-Quinase/metabolismo , Condicionamento Físico Animal/métodos , Precursores de Proteínas/metabolismo , Ratos , Ratos Wistar

RESUMO

Fetal ethanol experience generates learning and memories capable to increase ethanol consummatory behaviors during infancy. Opioid system seems to be involved in mediating those alcohol-related behaviors. In this work, we proposed to study the impact of prenatal exposure to a moderate ethanol dose, upon ingestion of the drug and possible ethanol-induced molecular changes on opioid precursor peptides (POMC, Pro-enk and Pro-DYN) and receptors (MOR, DOR and KOR) mRNA expression, in hypothalamus. Pregnant rats received during gestational days (GDs) 17-20, a daily intragastric (i.g.) administration with 2g/kg ethanol or water. A third group of dams was left undisturbed during pregnancy (Unmanipulated group). Intake test was conducted at postnatal days (PDs) 14-15. Three groups of pups were performed: control (no intake test), water (vehicle) and 5% ethanol. At the end of intake test blood samples were taken to quantify blood ethanol concentrations (BECs) and hypothalamus sections were obtained to perform qRT-PRC assessment of opioid precursor peptides and receptors. The analysis of the consummatory responses (% of consumption) and pharmacokinetic profiles (BECs) suggested that maternal manipulation induced by i.g. intubations, during the last four days of gestation (whenever ethanol or water), are sufficient to induce infantile ethanol intake during infancy. Gene expression from the hypothalamus of unmanipulated group revealed that infantile ingestive experiences with ethanol can down-regulate expression of mRNA Pro-Dyn and up-regulate mRNA expression of MOR and KOR. Finally, MOR mRNA expression was attenuated by prenatal i.g. manipulation in pups exposed to 5% ethanol.

Assuntos

Consumo de Bebidas Alcoólicas/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores Opioides/efeitos dos fármacos , Analgésicos Opioides/metabolismo , Animais , Animais Recém-Nascidos , Etanol/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Peptídeos Opioides , Gravidez , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Opioides/genética , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética

RESUMO

BACKGROUND: The endogenous opioid peptide system has been implicated in the neural modulation of fear and anxiety organised by the dorsal midbrain. Furthermore, previous results indicate a fundamental role played by inferior colliculus (IC) opioid mechanisms during the expression of defensive behaviours, but the involvement of the IC µ1-opioid receptor in the modulation of anxiety- and panic attack-related behaviours remains unclear. Using a prey-versus-snake confrontation paradigm, we sought to investigate the effects of µ1-opioid receptor blockade in the IC on the defensive behaviour displayed by rats in a dangerous situation. METHODS: Specific pathogen-free Wistar rats were treated with microinjection of the selective µ1-opioid receptor antagonist naloxonazine into the IC at different concentrations (1.0, 3.0 and 5.0 µg/0.2 µL) and then confronted with rattlesnakes ( Crotalus durissus terrificus). The defensive behavioural repertoire, such as defensive attention, flat back approach (FBA), startle, defensive immobility, escape or active avoidance, displayed by rats either during the confrontations with wild snakes or during re-exposure to the experimental context without the predator was analysed. RESULTS: The blockade of µ1-opioid receptors in the IC decreased the expression of both anxiety-related behaviours (defensive attention, FBA) and panic attack-related responses (startle, defensive immobility and escape) during the confrontation with rattlesnakes. A significant decrease in defensive attention was also recorded during re-exposure of the prey to the experimental apparatus context without the predator. CONCLUSION: Taken together, these results suggest that a decrease in µ1-opioid receptor signalling activity within the IC modulates anxiety- and panic attack-related behaviours in dangerous environments.

Assuntos

Ansiedade/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Medo , Colículos Inferiores/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Transtorno de Pânico/prevenção & controle , Receptores Opioides mu/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Crotalus , Modelos Animais de Doenças , Cadeia Alimentar , Naloxona/análogos & derivados , Naloxona/farmacologia , Ratos , Ratos Wistar

RESUMO

BACKGROUND: There is a controversy regarding the key role played by opioid peptide neurotransmission in the modulation of panic-attack-related responses. AIMS: Using a prey versus rattlesnakes paradigm, the present work investigated the involvement of the endogenous opioid peptide-mediated system of the inferior colliculus in the modulation of panic attack-related responses. METHODS: Wistar rats were pretreated with intracollicular administration of either physiological saline or naloxone at different concentrations and confronted with rattlesnakes ( Crotalus durissus terrificus). The prey versus rattlesnake confrontations were performed in a polygonal arena for snakes. The defensive behaviors displayed by prey (defensive attention, defensive immobility, escape response, flat back approach and startle) were recorded twice: firstly, over a period of 15 min the presence of the predator and a re-exposure was performed 24 h after the confrontation, when animals were exposed to the experimental enclosure without the rattlesnake. RESULTS: The intramesencephalic non-specific blockade of opioid receptors with microinjections of naloxone at higher doses decreased both anxiety- (defensive attention and flat back approach) and panic attack-like (defensive immobility and escape) behaviors, evoked in the presence of rattlesnakes and increased non-defensive responses. During the exposure to the experimental context, there was a decrease in duration of defensive attention. CONCLUSIONS: These findings suggest a panicolytic-like effect of endogenous opioid receptors antagonism in the inferior colliculus on innate (panic attack) and conditioned (anticipatory anxiety) fear in rats threatened by rattlesnakes.

Assuntos

Medo/efeitos dos fármacos , Colículos Inferiores/efeitos dos fármacos , Naloxona/farmacologia , Peptídeos Opioides/fisiologia , Transtorno de Pânico/tratamento farmacológico , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Crotalus , Mecanismos de Defesa , Reação de Fuga/efeitos dos fármacos , Medo/psicologia , Colículos Inferiores/fisiologia , Masculino , Peptídeos Opioides/antagonistas & inibidores , Ratos , Ratos Wistar

RESUMO

Considering the involvement of the opioid system in major depressive disorder (MDD), mainly concerning refractory MDD, and the evidence that ascorbic acid may exert a beneficial effect for the treatment of this disorder, this study investigated the involvement of the opioid system in the antidepressant-like effect of ascorbic acid in the tail suspension test (TST). Treatment of Swiss mice with the non-selective opioid receptor antagonist naloxone (1 mg/kg, i.p.) prevented the reduced immobility time caused by ascorbic acid (1 mg/kg, p.o.) in the TST. Additionally, administration of the selective µ1-opioid receptor antagonist, naloxonazine (10 mg/kg, i.p.), also abolished the antidepressant-like action of the same dose of ascorbic acid in the TST. We also investigated the possible relationship between the opioid system and NMDA receptors in the mechanism of action of ascorbic acid or ketamine (0.1 mg/kg, i.p.) in the TST. Treatment of mice with naloxone (1 mg/kg, i.p.) blocked the synergistic antidepressant-like effect of ascorbic acid (0.1 mg/kg. p.o.) and MK-801 (0.001 mg/kg, p.o., a non-competitive NMDA receptor antagonist) in the TST. Combined administration of ketamine and MK-801 induced a synergistic antidepressant-like action, and naloxone partially abolished this effect. Our results indicate that the antidepressant-like effect of ascorbic acid in the TST appears to be dependent on the activation of the opioid system, especially µ1-opioid receptors, which might be an indirect consequence of NMDA receptor inhibition elicited by ascorbic acid administration.

Assuntos

Antidepressivos/uso terapêutico , Ácido Ascórbico/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Animais , Antidepressivos/farmacologia , Ácido Ascórbico/farmacologia , Transtorno Depressivo Maior/psicologia , Feminino , Elevação dos Membros Posteriores/métodos , Elevação dos Membros Posteriores/psicologia , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Receptores Opioides/agonistas , Receptores Opioides/metabolismo

RESUMO

Animal and clinical researches indicate that the opioid system exerts a crucial role in the etiology of mood disorders and is a target for intervention in depression treatment. This study investigated the contribution of the opioid system to the antidepressant-like action of acute or repeated m-trifluoromethyl-diphenyl diselenide administration to Swiss mice. m-Trifluoromethyl-diphenyl diselenide (50 mg/kg, intragastric) produced an antidepressant-like action in the forced swimming test from 30 min to 24 h after treatment. This effect was blocked by the µ and δ-opioid receptor antagonists, naloxonazine (10 mg/kg, intraperitoneally) and naltrindole (3 mg/kg, intraperitoneally), and it was potentiated by a κ-opioid receptor antagonist, norbinaltrophimine (1 mg/kg, subcutaneously ). Combined treatment with subeffective doses of m-trifluoromethyl-diphenyl diselenide (10 mg/kg, intragastric) and morphine (1 mg/kg, subcutaneously) resulted in a synergistic antidepressant-like effect. The opioid system contribution to the m-trifluoromethyl-diphenyl diselenide antidepressant-like action was also demonstrated in the modified tail suspension test, decreasing mouse immobility and swinging time and increasing curling time, results similar to those observed using morphine, a positive control. Treatment with m-trifluoromethyl-diphenyl diselenide induced neither tolerance to the antidepressant-like action nor physical signs of withdrawal, which could be associated with the fact that m-trifluoromethyl-diphenyl diselenide did not change the mouse cortical and hippocampal glutamate uptake and release. m-Trifluoromethyl-diphenyl diselenide treatments altered neither locomotor nor toxicological parameters in mice. These findings demonstrate that m-trifluoromethyl-diphenyl diselenide elicited an antidepressant-like action by direct or indirect µ and δ-opioid receptor activation and the κ-opioid receptor blockade, without inducing tolerance, physical signs of withdrawal and toxicity.

Assuntos

Analgésicos Opioides/farmacologia , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Compostos de Organossilício/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Depressão/metabolismo , Transtorno Depressivo/metabolismo , Masculino , Camundongos , Morfina/farmacologia , Naloxona/análogos & derivados , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides kappa/metabolismo , Natação

RESUMO

D-limonene epoxidation generates (+)-limonene epoxide, an understudied compound in the pharmacologically point of view. Herein, we investigated the anti-inflammatory and antinociceptive potentialities of (+)-limonene epoxide and suggested a mechanism of action. The anti-inflammatory potential was analyzed using agents to induce paw edema, permeability, and myeloperoxidase (MPO) activity. Pro-inflammatory cytokines and cell migration of peritoneal cells were also assessed. Antinociceptive effects were evaluated by writhing test induced by acetic acid, formalin, and hot plate assays and contribution of opioid pathways. Pretreated animals with (+)-limonene epoxide showed reduced carrageenan-induced paw edema in all doses (25, 50, and 75 mg/kg) (P < 0.05). At 75 mg/kg, it suppressed edema provoked by compound 48/80, histamine, prostaglandin E2, and serotonin and reduced permeability determined by Evans blue and MPO activity. It also reduced leukocytes, neutrophils, and IL-1ß levels in the peritoneal cavity in comparison with carrageenan group (P < 0.05). (+)-Limonene epoxide diminished abdominal contortions induced by acetic acid (78.9%) and paw licking times in both 1 (41.8%) and 2 (51.5%) phases and a pretreatment with naloxone (3 mg/kg) reverted the antinociceptive action in morphine- and (+)-limonene epoxide-treated groups (P < 0.05). Additionally, it enlarged response times to the thermal stimulus after 60 and 90 min. In conclusion, (+)-limonene epoxide inhibited release/activity of inflammatory mediators, vascular permeability, migration of neutrophils and displayed systemic and peripheral analgesic-dependent effects of the opioid system.

Assuntos

Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Monoterpenos/farmacologia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Monoterpenos Cicloexânicos , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Mediadores da Inflamação , Masculino , Camundongos , Monoterpenos/uso terapêutico , Neutrófilos/citologia , Dor/tratamento farmacológico

RESUMO

Maternal separation alters the activity of the opioid system, which modulates ethanol-induced stimulation and behavioral sensitization. This study examined the effects of an opioid antagonist, naltrexone (NTX), on the expression of behavioral sensitization to ethanol in adult male and female mice submitted to maternal separation from postnatal days (PNDs) 2 to 14. Whole litters of Swiss mice were either not separated [animal facility rearing (AFR)] or separated from their mothers for 3 h [long maternal separation (LMS)]. Starting on PND 90, male and female AFR and LMS mice received daily i.p. injections of saline (SAL) or ethanol (EtOH, 2.2 g/kg) for 21 days. Locomotor activity was assessed in cages containing photoelectric beams, once a week, to examine the development of behavioral sensitization. Five days after the end of the chronic treatment, animals were submitted to four locomotor activity tests spaced by 48 h, to assess the expression of behavioral sensitization. In all tests, animals received two i.p. injections with a 30-min interval and were then assessed for locomotor response to different treatment challenges, which were: SAL/SAL, SAL/EtOH (2.2 g/kg), NTX 2.0 mg/kg (NTX2)/EtOH, and NTX 4.0 mg/kg (NTX4)/EtOH. Regardless of maternal separation, EtOH-treated male and female mice displayed increased locomotor responses to EtOH during the 21-day treatment, indicating the development of behavioral sensitization. In the SAL/EtOH challenge, EtOH-treated LMS and AFR male and female mice exhibited higher locomotor activity than their SAL-treated counterparts, indicating the expression of sensitization. The coadministration of either dose of NTX blocked the expression of locomotor sensitization in both AFR and LMS male mice with a history of EtOH sensitization. In females, a significant attenuation of EtOH sensitization was promoted by both NTX doses, while still maintaining an augmented stimulant response to EtOH. Importantly, maternal separation did not interfere in this phenomenon. These results indicate that expression of behavioral sensitization was importantly modulated by opioidergic mechanisms both in male and female mice and that maternal separation did not play a major role in either development or expression of this EtOH sensitization.