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1.
Behav Brain Res ; 436: 114087, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36057379

RESUMO

BACKGROUND: The phenomenon of alcohol analgesia and tolerance can facilitate misuse and lead to the development of alcohol use disorder (AUD). Numerous alcohol-induced behaviors are genetically influenced; however, it is unknown if alcohol analgesia has a genetic contribution. Rodent studies have shown that alcohol responses differ vastly between two widely studied inbred strains of mice, C57BL/6 J (B6) and DBA/2 J (D2). Here, we used B6 and D2 mice as an initial behavioral genetic analysis of acute alcohol-induced antinociception. METHODS: The antinociceptive effect of orally-administered alcohol was characterized using the hot plate test in B6 and D2 mice of both sexes. Using the opioid receptor antagonist naloxone, the involvement of the opioid system was assessed. Locomotor activity and blood alcohol concentrations were also measured. Ovariectomized mice were used to evaluate the influence of ovarian sex hormones on alcohol-induced antinociception. RESULTS: Alcohol induced an antinociceptive effect in B6 and D2 male mice in a time- and dose-dependent manner. In addition, D2 male mice were more sensitive to the antinociceptive effect of alcohol than B6 male mice. However, locomotion is not impeded by the tested doses of alcohol in B6 mice. Female D2 and B6 mice failed to show significant antinociceptive effects in alcohol dose-response studies. In addition, alcohol-induced antinociception was still not evident in ovariectomized female mice. Male mice of both strains developed tolerance to this effect after repeated administration of alcohol. Strain differences were found in blood alcohol concentration. Finally, no difference was found in the blockade of alcohol antinociception by 2 mg/kg naloxone. CONCLUSION: Our results indicate that the antinociceptive effects of alcohol in the hot plate test are influenced by strain and sex. These findings support further genetic analysis of alcohol-induced antinociception to identify operative mechanisms and better assess the contribution of this phenotype to AUD.


Assuntos
Alcoolismo , Concentração Alcoólica no Sangue , Analgésicos Opioides , Animais , Etanol/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/tratamento farmacológico
2.
J Ethnopharmacol ; 300: 115756, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36170958

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Rhus genus is commonly known as sumac and widely used in the folk medicine. Rhus virens is a plant commonly used to treat diabetes or pain in the northern territory of Mexico. Even though R. virens is used in the folk medicine there is still a lack of evidence about the pharmacological effect of this species. AIM OF THE STUDY: The aim of this study was to determine the antinociceptive, anti-inflammatory and antioxidant effect of R. virens through a bio-guided chemical separation. MATERIALS AND METHODS: The aqueous, methanolic, and hexane extract of R. virens were obtained and tested in the formalin test, TPA-induced ear edema, and DPPH, ABTS, and FRAP assay. Also, possible interaction of pain pathways was studied using naloxone, bicuculline, L-NAME, ODQ, and glibenclamide in the formalin test in mice. RESULTS: Rhus virens methanolic extract (30 mg/kg, p.o.) produced higher antinociceptive activity in both the early and late phases of the formalin test (35.0 and 52.9%, respectively). Also, pre-administration with naloxone, bicuculline, L-NAME, ODQ and glibenclamide prevented the antinociceptive effect of R. virens in the early phase of the formalin test. Meanwhile, only naloxone and bicuculline prevented the antinociceptive effect on the late phase of the formalin test. Chemical separation of methanolic extract allowed to isolate 1,2,3,4,6-penta-O-galloyl-glucopyranose (PGG), it was tested in the formalin test, producing an antinociceptive effect on the late phase of the formalin test. On the other hand, topical application of the derivatives of R. virens methanolic extract produced an anti-inflammatory effect in the TPA-induced ear edema, being PGG an anti-inflammatory molecule. Lastly, radical scavenging activity was higher in the extracts of higher polarity, comparable to the standard used Camellia sinensis. CONCLUSIONS: In conclusion, R. virens produce an antinociceptive, anti-inflammatory and free-radical scavenging activity. The antinociceptive effect could be related to the opioidergic, GABAergic, and NO-GMPc-K + ATP channels pathways. These effects could be partially produced by the presence of PGG.


Assuntos
Rhus , Trifosfato de Adenosina , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Bicuculina , Edema/induzido quimicamente , Edema/tratamento farmacológico , Glibureto , Hexanos , Camundongos , NG-Nitroarginina Metil Éster , Naloxona/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de Planta/química
3.
Behav Brain Res ; 437: 114122, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36174840

RESUMO

Gender differences have been observed in the vulnerability to drug abuse and in the different stages of the addictive process. In opiate dependence, differences between sexes have been shown in humans and laboratory animals in various phases of opiate addiction, especially in withdrawal-associated negative affective states. Using a Y-maze conditioned place aversion paradigm, we investigated potential sex differences in the expression and extinction of the aversive memory of precipitated opiate withdrawal state in morphine-dependent rats. No significant difference between sexes was observed in the occurrence of withdrawal signs following naloxone injection during conditioning. Moreover, opiate withdrawal memory expression and extinction following repeated testing was demonstrated in both male and female rats, with no significant differences between sexes. Finally, we report spontaneous recovery following extinction of opiate withdrawal memory. Altogether these data provide further evidence that persistent withdrawal-related memories may be strong drivers of opiate dependence, and demonstrate that both males and females can be used in experimental rodent cohorts to better understand opiate-related effects, reward, aversive state of withdrawal, abstinence and relapse.


Assuntos
Dependência de Morfina , Alcaloides Opiáceos , Transtornos Relacionados ao Uso de Opioides , Síndrome de Abstinência a Substâncias , Humanos , Ratos , Animais , Feminino , Masculino , Síndrome de Abstinência a Substâncias/metabolismo , Aprendizagem da Esquiva , Naloxona/farmacologia , Analgésicos Opioides/farmacologia , Dependência de Morfina/metabolismo , Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia
4.
Bull Exp Biol Med ; 173(6): 730-733, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36322304

RESUMO

Activity of a peptide tuftsin analogue Selank was studied in outbred rats using the naloxone-precipitated morphine withdrawal model. Single intraperitoneal injection of Selank in an anxiolytic dose of 0.3 mg/kg reduced the total index of morphine withdrawal syndrome by 39.6%, significantly (р<0.0001) attenuated convulsive reactions, ptosis, and posture disorders, and 9-fold increased the tactile sensitivity threshold in morphine-dependent rats in comparison with the group of active control; at the same time, Selank was slightly inferior to diazepam in a dose of 2 mg/kg by pharmacological activity (the decrease in total index of morphine withdrawal syndrome by 49.3% and 13-fold increase in sensitivity threshold). Thus, Selank, like diazepam, weakens the aversive signs of morphine withdrawal in rats with opiate dependence.


Assuntos
Dependência de Morfina , Síndrome de Abstinência a Substâncias , Tuftsina , Ratos , Animais , Morfina , Dependência de Morfina/tratamento farmacológico , Naloxona/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Diazepam
5.
Biomed Environ Sci ; 35(9): 792-803, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36189994

RESUMO

Objective: This study aimed to investigate the effects of Montanide ISA-720 and Naloxone (NLX) in Hepatitis B surface antigen (HBsAg) vaccine formulation on cytokine and long-lasting antibody responses. Methods: First, the HBsAg was formulated in Montanide ISA-720 adjuvant and Naloxone at 5 and 10 mg/kg. The experimental mice were immunized three times at a 2-week interval, and then IL-4, IL-2, TNF-α, and IFN-γ cytokines; long-lasting IgG antibody responses 220 days after the last shot; and IgG1/IgG2a isotypes were assessed by ELISA. Results: The HBsAg-Alum group exhibited the highest IL-4 cytokine response among the experimental groups, whereas NLX in HBsAg-MON720 vaccine formulation did not affect cytokine responses. In addition, NLX in Alum-based vaccine suppressed IL-4 cytokine response and increased the IL-2/IL-4 cytokine ratio. Moreover, HBsAg-MON720 was more potent than HBsAg-Alum in the induction of antibody responses, and NLX in Alum- and MON720-based vaccines induced long-lasting antibody responses. Conclusion: NLX in Alum-based vaccine decreased IL-4 cytokine response, increased IL-2/IL-4 cytokine ratio, and improved long-lasting humoral immune responses in both vaccine formulations. Therefore, the adjuvant activity of NLX in the vaccine formulation depends on the type of adjuvant and the nature of the antigen in the vaccine formulation.


Assuntos
Antígenos de Superfície da Hepatite B , Imunidade Humoral , Adjuvantes Imunológicos/farmacologia , Compostos de Alúmen , Animais , Citocinas , Vacinas contra Hepatite B , Imunoglobulina G , Interleucina-2 , Interleucina-4 , Camundongos , Camundongos Endogâmicos BALB C , Óleo Mineral , Naloxona/farmacologia , Fator de Necrose Tumoral alfa
6.
Int J Mol Sci ; 23(19)2022 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-36232988

RESUMO

In this work we strived to determine whether endocannabinoid system activity could account for the differences in acute inflammatory pain sensitivity in mouse lines selected for high (HA) and low (LA) swim-stress-induced analgesia (SSIA). Mice received intraplantar injections of 5% formalin and the intensity of nocifensive behaviours was scored. To assess the contribution of the endocannabinoid system, mice were intraperitoneally (i.p.) injected with rimonabant (0.3-3 mg/kg) prior to formalin. Minocycline (45 and 100 mg/kg, i.p.) was administered to investigate microglial activation. The possible involvement of the endogenous opioid system was investigated with naloxone (1 mg/kg, i.p.). Cannabinoid receptor types 1 and 2 (Cnr1, Cnr2) and opioid receptor subtype (Oprm1, Oprd1, Oprk1) mRNA levels were quantified by qPCR in the structures of the central nociceptive circuit. Levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by liquid chromatography coupled with the mass spectrometry method (LC-MS/MS). In the interphase, higher pain thresholds in the HA mice correlated with increased spinal anandamide and 2-AG release and higher Cnr1 transcription. Downregulation of Oprd1 and Oprm1 mRNA was noted in HA and LA mice, respectively, however no differences in naloxone sensitivity were observed in either line. As opposed to the LA mice, inflammatory pain sensitivity in the HA mice in the tonic phase was attributed to enhanced microglial activation, as evidenced by enhanced Aif1 and Il-1ß mRNA levels. To conclude, Cnr1 inhibitory signaling is one mechanism responsible for decreased pain sensitivity in HA mice in the interphase, while increased microglial activation corresponds to decreased pain thresholds in the tonic inflammatory phase.


Assuntos
Analgesia , Endocanabinoides , Analgésicos Opioides/farmacologia , Animais , Ácidos Araquidônicos , Cromatografia Líquida , Endocanabinoides/farmacologia , Formaldeído/farmacologia , Camundongos , Microglia , Minociclina/farmacologia , Naloxona/farmacologia , Dor/genética , Limiar da Dor , Alcamidas Poli-Insaturadas , Receptores de Canabinoides , Receptores Opioides/genética , Rimonabanto/farmacologia , Espectrometria de Massas em Tandem
7.
J Neurophysiol ; 128(5): 1117-1132, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36197016

RESUMO

Opioids suppress breathing through actions in the brainstem, including respiratory-related areas of the dorsolateral pons, which contain multiple phenotypes of respiratory patterned neurons. The discharge identity of dorsolateral pontine neurons that are impacted by opioids is unknown. To address this, single neuronal units were recorded in the dorsolateral pons of arterially perfused in situ rat preparations that were perfused with an apneic concentration of the opioid agonist fentanyl, followed by the opioid antagonist naloxone (NLX). Dorsolateral pontine neurons were categorized based on respiratory-associated discharge patterns, which were differentially affected by fentanyl. Inspiratory neurons and a subset of inspiratory/expiratory phase-spanning neurons were either silenced or had reduced firing frequency during fentanyl-induced apnea, which was reversed upon administration of naloxone. In contrast, the majority of expiratory neurons continued to fire tonically during fentanyl-induced apnea, albeit with reduced firing frequency. In addition, pontine late-inspiratory and postinspiratory neuronal activity were absent from apneustic-like breaths during the transition to fentanyl-induced apnea and the naloxone-mediated transition to recovery. Thus, opioid-induced deficits in respiratory patterning may occur due to reduced activity of pontine inspiratory neurons, whereas apnea occurs with loss of all phasic pontine activity and sustained tonic expiratory neuron activity.NEW & NOTEWORTHY Opioids can suppress breathing via actions throughout the brainstem, including the dorsolateral pons. The respiratory phenotype of dorsolateral pontine neurons inhibited by opioids is unknown. Here, we describe the effect of the highly potent opioid fentanyl on the firing activity of these dorsolateral pontine neurons. Inspiratory neurons were largely silenced by fentanyl, whereas expiratory neurons were not. We provide a framework whereby this differential sensitivity to fentanyl can contribute to respiratory pattern deficits and apnea.


Assuntos
Analgésicos Opioides , Apneia , Ratos , Animais , Analgésicos Opioides/farmacologia , Fentanila/farmacologia , Ponte/fisiologia , Neurônios/fisiologia , Respiração , Naloxona/farmacologia
8.
ACS Chem Neurosci ; 13(21): 3108-3117, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36223082

RESUMO

The opioid crisis continues to claim many lives, with a particular issue being the ready availability and use (whether intentional or accidental) of fentanyl and fentanyl analogues. Fentanyl is both potent and longer-acting than naloxone, the standard of care for overdose reversal, making it especially deadly. Consequently, there is interest in opioid reversal agents that are better able to counter its effects. The orvinol series of ligands are known for their high-affinity binding to opioid receptors and often extended duration of action; generally, compounds on this scaffold show agonist activity at the kappa and the mu-opioid receptor. Diprenorphine is an unusual member of this series being an antagonist at mu and only a partial agonist at kappa-opioid receptors. In this study, an orvinol antagonist, 14, was designed and synthesized that shows no agonist activity in vitro and is at least as good as naloxone at reversing the effects of mu-opioid receptor agonists in vivo.


Assuntos
Antagonistas de Entorpecentes , Overdose de Opiáceos , Humanos , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides mu/metabolismo , Naloxona/farmacologia , Receptores Opioides kappa/metabolismo , Receptores Opioides/metabolismo , Fentanila/farmacologia , Analgésicos Opioides/farmacologia
9.
Psychopharmacology (Berl) ; 239(12): 3939-3952, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36287213

RESUMO

RATIONALE: Adolescents represent a vulnerable group due to increased experimentation with illicit substances that is often associated with the adolescent period, and because adolescent drug use can result in long-term effects that differ from those caused by drug use initiated during adulthood. OBJECTIVES: The purpose of the present study was to determine the effects of repeated heroin vapor inhalation during adolescence on measures of nociception, and anxiety-like behavior during adulthood in female and male Wistar rats. METHODS: Rats were exposed twice daily to 30 min of heroin vapor from post-natal day (PND) 36 to PND 45. At 12 weeks of age, baseline thermal nociception was assessed across a range of temperatures with a warm-water tail-withdrawal assay. Anxiety-like behavior was assessed in an elevated plus-maze (EPM) and activity was measured in an open-field arena. Starting at 23 weeks of age, baseline thermal nociception was re-assessed, nociception was determined after acute heroin or naloxone injection, and anxiety-like behavior was redetermined in the EPM. RESULTS: Adolescent heroin inhalation altered baseline thermal nociception in female rats at 12 weeks of age and in both female and male rats at ~ 23 weeks. Heroin-treated animals exhibited anxiety-like behavior when tested in the elevated plus-maze, showed blunted heroin-induced analgesia, but exhibited no effect on naloxone-induced hyperalgesia. CONCLUSIONS: The present study demonstrates that heroin vapor inhalation during adolescence produces behavioral and physiological consequences in rats that persist well into adulthood.


Assuntos
Heroína , Nociceptividade , Ratos , Animais , Masculino , Feminino , Ratos Wistar , Heroína/farmacologia , Ansiedade , Naloxona/farmacologia
10.
Molecules ; 27(18)2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36144565

RESUMO

Numerous G-protein-coupled receptors (GPCRs) display ligand-free basal signaling with potential physiological functions, a target in drug development. As an example, the µ opioid receptor (MOR) signals in ligand-free form (MOR-µ*), influencing opioid responses. In addition, agonists bind to MOR but can dissociate upon MOR activation, with ligand-free MOR-µ* carrying out signaling. Opioid pain therapy is effective but incurs adverse effects (ADRs) and risk of opioid use disorder (OUD). Sustained opioid agonist exposure increases persistent basal MOR-µ* activity, which could be a driving force for OUD and ADRs. Antagonists competitively prevent resting MOR (MOR-µ) activation to MOR-µ*, while common antagonists, such as naloxone and naltrexone, also bind to and block ligand-free MOR-µ*, acting as potent inverse agonists. A neutral antagonist, 6ß-naltrexol (6BN), binds to but does not block MOR-µ*, preventing MOR-µ activation only competitively with reduced potency. We hypothesize that 6BN gradually accelerates MOR-µ* reversal to resting-state MOR-µ. Thus, 6BN potently prevents opioid dependence in rodents, at doses well below those blocking antinociception or causing withdrawal. Acting as a 'retrograde addiction modulator', 6BN could represent a novel class of therapeutics for OUD. Further studies need to address regulation of MOR-µ* and, more broadly, the physiological and pharmacological significance of ligand-free signaling in GPCRs.


Assuntos
Analgesia , Transtornos Relacionados ao Uso de Opioides , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Humanos , Ligantes , Morfina/farmacologia , Naloxona/farmacologia , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Dor/tratamento farmacológico , Receptores Opioides mu/metabolismo
11.
Molecules ; 27(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36080199

RESUMO

The current work examined the pharmacological potential of a selected flavanone derivative 2-hydroxyflavanone as a promising remedy for the treatment and management of pain. The selected flavanone derivative (2-HF) was evaluated for its analgesic and anti-inflammatory potentials following standard pharmacological protocols including hot plate, acetic acid-induced writhing and tail immersion tests. Naloxone and pentylenetetrazol were used to evaluate the potential implication of GABAergic and opioidergic mechanisms. The anti-inflammatory potential of 2-HF was confirmed using carrageenan-, serotonin- and histamine-induced paw edema models as well as a xylene-induced ear edema model. Furthermore, the anti-neuropathic potential of 2-HF was tested using a cisplatin-induced neuropathic pain model. Our sample, at the tested concentrations of 15, 30 and 45 mg kg-1, showed considerable analgesic, anti-inflammatory effects, as well as efficacy against neuropathic pain. Naloxone and pentylenetetrazol at 1 and 15 mg kg-1 antagonized the anti-nociceptive activities of 2-hydroxyflavanone indicating the involvement of opioidergic and GABAergic mechanisms. In the static allodynia model, combination of gabapentin 75 mg kg-1 with 2-HF at 15, 30, 45 mg kg-1 doses exhibited considerable efficacy. In cold allodynia, 2-hydroxyflavanone, at doses of 15, 30 and 45 mg kg-1 and in combination with gabapentin (75 mg kg-1), demonstrated prominent anti-allodynic effects. The paw withdrawal latency was considerably increased in gabapentin + cisplatin treated groups. Moreover, cisplatin + 2-hydroxyflavanone 15, 30, 45 mg kg-1 showed increases in paw withdrawal latency. Likewise, considerable efficacy was observed for 2-hydroxyflavanone in thermal hyperalgesia and dynamic allodynia models. Our findings suggest that 2-hydroxyflavanone is a potential remedy for pain syndrome, possibly mediated through opioidergic and GABAergic mechanisms.


Assuntos
Flavanonas , Neuralgia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/efeitos adversos , Cisplatino/efeitos adversos , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Flavanonas/uso terapêutico , Gabapentina/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Naloxona/farmacologia , Naloxona/uso terapêutico , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Pentilenotetrazol/efeitos adversos , Roedores
12.
Brain Behav Immun ; 106: 180-197, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36058417

RESUMO

Major depressive disorder (MDD) is a debilitating disease with a high worldwide prevalence. Despite its greater prevalence in women, male animals are used in most preclinical studies of depression even though there are many sex differences in key components of depression, such as stress responses and immune system functions. In the present study, we found that chronic restraint stress-induced depressive-like behaviors are quite similar in male and female mice, with both sexes displaying increased immobility time in the tail suspension test and reduced social interactions, and both sexes exhibited deficits in working and spatial memories. However, in contrast to the similar depressive-like behaviors developed by male and female mice in response to stress, they displayed different patterns of pro-inflammatory cytokine increases in the periphery and the brain, different changes in microglia, and different changes in the expression of Toll-like receptor 4 in response to stress. Treatment with (+)-naloxone, a Toll-like receptor 4 antagonist that previously demonstrated anti-depressant-like effects in male mice, was more efficacious in male than female mice in reducing the deleterious effects of stress, and its effects were not microbiome-mediated. Altogether, these results suggest differential mechanisms to consider in potential sex-specific treatments of depression.


Assuntos
Transtorno Depressivo Maior , Receptor 4 Toll-Like , Animais , Comportamento Animal , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Naloxona/farmacologia , Estresse Psicológico/tratamento farmacológico
13.
Neurogastroenterol Motil ; 34(11): e14442, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36054796

RESUMO

BACKGROUND: In most animal species, opioids alter colonic motility via the inhibition of excitatory enteric motor neurons. The mechanisms by which opioids alter human colonic motility are unclear. The aim of this study was to describe the effects of loperamide on neuromuscular function in the human colon. METHODS: Tissue specimens of human colon from 10 patients undergoing an anterior resection were divided into three inter-taenial circular muscle strips. Separate organ baths were used to assess: (1) excitatory transmission (selective blockade of inhibitory transmission: L-NOARG/MRS2179); (2) inhibitory transmission (selective blockade of excitatory transmission: hyoscine hydrobromide); and (3) a control bath (no drug additions). Neuromuscular function was assessed using force transducer recordings and electrical field stimulation (EFS; 20 V, 10 Hz, 0.5 ms, 10 s) prior to and following loperamide and naloxone. KEY RESULTS: In human preparations with L-NOARG/MRS2179, loperamide had no significant effects on isometric contractions. In preparations with hyoscine hydrobromide, loperamide reduced isometric relaxation during EFS (median difference + 0.60 g post-loperamide, Z = -2.35, p = 0.019). CONCLUSIONS AND INFERENCES: Loperamide had no effect on excitatory neuromuscular function in human colonic circular muscle. These findings suggest that loperamide alters colonic function by acting primarily on inhibitory motor neurons, premotor enteric neurons, or via alternative non-opioid receptor pathways.


Assuntos
Loperamida , Escopolamina , Animais , Colo , Estimulação Elétrica , Motilidade Gastrointestinal , Humanos , Loperamida/farmacologia , Contração Muscular/fisiologia , Naloxona/farmacologia , Nitroarginina/farmacologia , Escopolamina/farmacologia
14.
Biomed Pharmacother ; 155: 113671, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36108390

RESUMO

Osteoarthritis (OA) affects more than 300 million people worldwide and it is about to become the first disabling disease. OA is characterized by the progressive degradation of the articular cartilage but is a disease of the whole joint. Articular innate immune responses (IIR) associated with tissue degradation contribute to its progression. However, no treatment is available to block these IIRs. Through data text mining and computational pharmacology, we identified two clinical available drugs, naloxone, and thalidomide, with potential inhibitory properties on toll-like receptor 4 (TLR4), a major activator of these IIR. Proteome analysis confirmed that activation of this receptor or the IL1 receptor generated OA-like and gout-like proteomic changes in human primary chondrocytes. Both compounds were found to block TLR4 complex and inhibit TLR4 and IL1R-mediated IIR in OA chondrocytes, osteoblasts, and synoviocytes. Furthermore, naloxone and thalidomide inhibitory effects involved the downregulation of the NLRP3 inflammasome pathway, which is downstream of TLR4/IL1R signaling. We demonstrated that these compounds, within a therapeutic range of concentrations, exhibited anti-inflammatory and anti-catabolic properties in joint primary OA cells without any toxic effect. This data underpins naloxone & thalidomide repurpose to treat OA-associated inflammatory responses.


Assuntos
Osteoartrite , Receptor 4 Toll-Like , Humanos , Condrócitos/metabolismo , Reposicionamento de Medicamentos , Imunidade Inata , Inflamassomos/metabolismo , Naloxona/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteoartrite/metabolismo , Proteoma/metabolismo , Proteômica , Receptores de Interleucina-1/metabolismo , Talidomida/farmacologia , Receptor 4 Toll-Like/metabolismo , Interleucina-1/metabolismo
15.
Neuroreport ; 33(16): 681-689, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36165043

RESUMO

The involvement of the opioidergic system on anxiolytic and antinociceptive responses induced by cholestasis was investigated in cholestatic and addicted mice. Elevated plus-maze and tail-flick devices were used to assess anxiety and pain levels, respectively. The data indicated that induction of cholestasis and injection of opioid drugs including morphine and tramadol enhanced %OAT and %OAE but naloxone reduced %OAT and %OAE in the sham-operated and bile duct ligation (BDL) mice. Induction of cholestasis and addiction to morphine and tramadol prolonged tail-flick latency, which was reversed by naloxone. Coadministration of morphine and tramadol enhanced anxiolytic and analgesic effects in the sham-operated and BDL mice. It seems (a) cholestasis and addiction affect anxiety and pain behaviors, (b) µ-opioid receptors play a key role in anxiolytic and analgesic effects induced by cholestasis, and (c) cotreatment with morphine and tramadol augmented the effectiveness of them for induction of anxiolytic and analgesic effects both in cholestatic and addicted mice.


Assuntos
Ansiolíticos , Colestase , Tramadol , Animais , Camundongos , Analgésicos Opioides/farmacologia , Ansiolíticos/uso terapêutico , Colestase/complicações , Colestase/tratamento farmacológico , Relação Dose-Resposta a Droga , Morfina/farmacologia , Naloxona/farmacologia , Naloxona/uso terapêutico , Dor/tratamento farmacológico , Receptores Opioides mu
16.
J Pineal Res ; 73(4): e12825, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35996205

RESUMO

Melatonin, through its G protein-coupled receptor (GPCR) (MTNR1B gene) MT2 , is implicated in analgesia, but the relationship between MT2 receptors and the opioid system remains elusive. In a model of rodent neuropathic pain (spared nerve injured [SNI]), the selective melatonin MT2 agonist UCM924 reversed the allodynia (a pain response to a non-noxious stimulus), and this effect was nullified by the pharmacological blockade or genetic inactivation of the mu opioid receptor (MOR), but not the delta opioid receptor (DOR). Indeed, SNI MOR, but not DOR knockout mice, did not respond to the antiallodynic effects of the UCM924. Similarly, the nonselective opioid antagonist naloxone and the selective MOR antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) blocked the effects of UCM924 in SNI rats, but not the DOR antagonist naltrindole (NTI). Electrophysiological recordings in the rostral-ventromedial medulla (RVM) revealed that the typical reduction of the firing activity of pronociceptive ON-cells, and the enhancement of the firing of the antinociceptive OFF-cells, induced by the microinjection of the MT2 agonist UCM924 into the ventrolateral periaqueductal gray (vlPAG) were blocked by MOR, but not DOR, antagonism. Immunohistochemistry studies showed that MT2 receptors are expressed in both excitatory (CaMKIIα+ ) and inhibitory (GAD65+ ) neuronal cell bodies in the vlPAG (~2.16% total), but not RVM. Only 0.20% of vlPAG neurons coexpressed MOR and MT2 receptors. Finally, UCM924 treatment induced an increase in the enkephalin precursor gene (PENK) in the PAG of SNI mice. Collectively, the melatonin MT2 receptor agonism requires MORs to exert its antiallodynic effects, mostly through an interneuronal circuit involving MOR and MT2 receptors.


Assuntos
Melatonina , Neuralgia , Camundongos , Animais , Ratos , Receptores Opioides mu/genética , Receptores Opioides mu/agonistas , Melatonina/farmacologia , Melatonina/uso terapêutico , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/uso terapêutico , Receptores Opioides delta , Analgésicos Opioides/uso terapêutico , Encefalinas/farmacologia , Encefalinas/uso terapêutico , Naloxona/farmacologia , Naloxona/uso terapêutico , Neuralgia/tratamento farmacológico
17.
Eur J Med Chem ; 241: 114649, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-35961067

RESUMO

To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional µ opioid receptor (MOR) and σ1 receptor (σ1R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (Ki = 6.5 nΜ; EC50 = 48.5 nΜ, Emax = 66.3%) and σ1R antagonism (Ki = 35.7 nM) in vitro, and exerted powerful analgesic effects in the abdominal constriction test (ED50 = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED50 = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED50 = 0.30 mg/kg, in mice). The contributions of MOR and σ1R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ1R agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects-including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion-than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σ1R ligands as a promising avenue for the development of potent and safe analgesics.


Assuntos
Analgésicos , Neuralgia , Receptores Opioides mu , Receptores sigma , Analgésicos/farmacologia , Animais , Ligantes , Camundongos , Naloxona/farmacologia , Ratos , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores
18.
Behav Brain Res ; 435: 114046, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-35933048

RESUMO

Plenty information exists regarding the effects of chronic stress, although few data exist on the effects of short-lasting stressors, which would mimic daily challenges. Differences in craniofacial and spinal nociception have been observed, thus those observations obtained in spinally innervated areas cannot be directly applied to the orofacial region. Although, opioids are considered amongst the most effective analgesics, their use is sometimes hampered by the constipation they induce. Thus, our aims were to study if a short-lasting stressor, forced swim stress (FSS), modifies nociception, morphine antinociception and constipation in rats. Animals were submitted to 10-20 min of FSS for three days, nociception and gastrointestinal transit were studied 24 h after the last swimming session. Nociception and morphine (0.6-5 mg/kg) antinociception were evaluated in the formalin and hypertonic saline tests in the orofacial area and limbs. Morphine-induced modifications in the GI transit were studied through radiographic techniques. Naloxone was administered, before each swimming session, to analyse the involvement of the endogenous opioid system on the effect of stress. Overall, stress did not alter nociception, although interestingly it reduced the effect of morphine in the orofacial tests and in the inflammatory phase of the formalin tests. Naloxone antagonized the effect of stress and normalized the effect of morphine. Stress did not modify the constipation induced by morphine. Opioid treatment may be less effective under a stressful situation, whilst adverse effects, such as constipation, are maintained. The prevention of stress may improve the level of opioid analgesia.


Assuntos
Analgesia , Morfina , Analgésicos Opioides/farmacologia , Animais , Constipação Intestinal , Morfina/farmacologia , Naloxona/farmacologia , Dor , Ratos
19.
J Addict Med ; 16(6): e399-e404, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35916423

RESUMO

OBJECTIVES: Data regarding treatment outcomes with the use of buprenorphine-naloxone (BUP-NX) in pregnancy are scarce. The objective of this study is to examine the outcomes in a cohort of pregnancies treated with BUP-NX versus buprenorphine (BUP). METHODS: This single-center, retrospective cohort study examined birthing person-infant dyads treated with BUP-NX versus BUP. The primary birthing person outcome was return to opioid use in pregnancy. The primary neonatal outcome was the need for pharmacologic treatment for neonatal opioid withdrawal syndrome (NOWS). RESULTS: The BUP-NX and the BUP treatment groups included 33 and 73 dyads, respectively. Except for psychiatric medication use, all demographics were similar between groups. In the final regression models, neither the birthing person nor the neonatal outcomes differed. The adjusted odds ratio for return to use during pregnancy for the BUP-NX versus BUP groups was 1.93 (95% confidence interval, 0.78-4.76). The adjusted odds ratio for pharmacologic treatment of NOWS for the BUP-NX versus BUP groups was 0.65 (95% confidence interval, 0.27-1.54). Among a subgroup of persons who transitioned from BUP to BUP-NX mid-pregnancy, there was no proximate return to use or need for dose increase. CONCLUSIONS: Compared with BUP, the use of BUP-NX in pregnancy is not associated with a higher risk of return to opioid use or a higher need for pharmacological treatment for NOWS.


Assuntos
Buprenorfina , Transtornos Relacionados ao Uso de Opioides , Recém-Nascido , Humanos , Gravidez , Feminino , Buprenorfina/uso terapêutico , Buprenorfina/farmacologia , Combinação Buprenorfina e Naloxona/uso terapêutico , Naloxona/uso terapêutico , Naloxona/farmacologia , Analgésicos Opioides/efeitos adversos , Estudos Retrospectivos , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/complicações , Tratamento de Substituição de Opiáceos
20.
J Ethnopharmacol ; 296: 115508, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35779820

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Eugenia uniflora (Myrtaceae) is a species native to Brazil and has a traditional use in the treatment of inflammation. AIM OF THE STUDY: To evaluate the anti-inflammatory and antinociceptive effects, and the involvement of opioid receptors in the antinociceptive activity of extract and fractions from Eugenia uniflora leaves. MATERIALS AND METHODS: TLC and HPLC were used to characterize the spray-dried extract (SDE) and fractions. In the in vivo assays, Swiss (Mus musculus) mice were used. Carrageenan-induced hind-paw edema and carrageenan-induced peritonitis models were used to determine the anti-inflammatory effect of the extract (50, 100, or 200 mg/kg). Acetic acid-induced writhing, tail-flick, and formalin tests were used to determine the antinociceptive effect of the extract (50, 100, or 200 mg/kg). The aqueous (AqF) and ethyl acetate (EAF) fractions (6.25, 12.5, and 25 mg/kg) were then combined with naloxone to evaluate the involvement of opioid receptors in the antinociceptive activity. RESULTS: In this work, the TLC and HPLC analysis evidenced the enrichment of EAF, which higher concentration of gallic acid (5.29 ± 0.0004 %w/w), and ellagic acid (1.28 ± 0.0002 %w/w) and mainly myricitrin (8.64 ± 0.0002 %w/w). The extract decreased the number of total leukocytes and neutrophils in the peritoneal cavity (p < 0.05), at doses of 100 and 200 mg/kg and showed significant inhibition in the increase of paw edema volume (p < 0.05). The treatment per oral route (doses of 50, 100, and 200 mg/kg) significantly reduced the nociceptive response in acetic acid-induced abdominal writhing (p < 0.05). The effect of the extract on the tail-flick test showed a significant increase in latency time of animals treated at doses of 200 and 100 mg/kg (p < 0.05). The extract and ethyl acetate fraction reduced the nociceptive effect in both phases of formalin at all tested doses. The naloxone reversed the antinociceptive effect of EAF, suggesting that opioid receptors are involved in mediating the antinociceptive activity of EAF of E. uniflora in the formalin test. CONCLUSION: The current study demonstrates the anti-inflammatory and analgesic activities of water: ethanol: propylene glycol spray-dried extract from E. uniflora leaves using in vivo pharmacological models in mice. Our findings suggest that spray-dried extract and ethyl acetate fraction exhibit peripheral and central antinociceptive activity with the involvement of opioid receptors that may be related to the presence of flavonoids, mainly myricitrin.


Assuntos
Eugenia , Ácido Acético/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carragenina , Edema/induzido quimicamente , Edema/tratamento farmacológico , Etanol/uso terapêutico , Camundongos , Naloxona/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Propilenoglicóis/efeitos adversos , Receptores Opioides , Água
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