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1.
Transl Psychiatry ; 11(1): 445, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471102

RESUMO

Dopamine (DA) neurotransmission is critical in the neurobiology of reward and aversion, but its contribution to the aversive state of opioid withdrawal remains unknown in humans. To address this, we used updated voxelwise methods and retrospectively analyzed a [11C]raclopride-PET dataset to measure D2/3 receptor availability and relative cerebral blood flow (R1) in male opioid use disorder (OUD) participants (n = 10) during placebo and acute opioid withdrawal conditions. We found that acute withdrawal precipitated by the opioid antagonist naloxone significantly increased dorsal striatal DA release in OUD participants (pFWE < 0.05). Net changes in striatal DA were significantly correlated with a subjective index of withdrawal aversion such that greater DA increases were associated with more aversive responses (r(8) = 0.82, p < 0.005). Withdrawal also affected brain function, as indexed by increases in relative cerebral blood flow in the insula and putamen (pFWE < 0.05). Our findings are different from preclinical studies that have primarily reported decreases in ventral striatal DA during naloxone precipitated withdrawal, whereas this effect was not significant in OUD participants (p = 0.79). In sum, we provide evidence for the contribution of increases in dorsal striatal DA to the aversive state of naloxone precipitated withdrawal in humans.


Assuntos
Síndrome de Abstinência a Substâncias , Estriado Ventral , Analgésicos Opioides/uso terapêutico , Dopamina , Humanos , Masculino , Naloxona/farmacologia , Naloxona/uso terapêutico , Estudos Retrospectivos , Síndrome de Abstinência a Substâncias/tratamento farmacológico
2.
Drug Alcohol Depend ; 227: 108974, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34492557

RESUMO

BACKGROUND: High doses of the synthetic opioid fentanyl cause rapid and sustained vocal cord closure (VCC) leading to airway obstruction that prevents overdose victims from breathing. This airway effect is not caused by morphine-derived opiates (e.g. heroin), is distinct from respiratory depression, resistant to naloxone, and can be lethal. However, VCC has not been previously included in animal models of opioid overdose. METHODS: Video laryngoscopy was used to monitor vocal cord movement in anesthetized Sprague-Dawley rats. Rats were administered saline, fentanyl (5, 25, or 50 µg/kg) or morphine (5 mg/kg) in an intravenous (IV) bolus delivered over a 10 s period. The mu opioid receptor (MOR) antagonist naloxone was administered as a pre-treatment (1 mg/kg, IV) 5 min prior to fentanyl (25 µg/kg) or a post-treatment (1 and 2 mg/kg) 1 min after fentanyl (25 µg/kg). RESULTS: Fentanyl (25 and 50 µg/kg) caused sustained and lethal VCC within 10 s. Morphine (5 mg/kg) and fentanyl (5 µg/kg) caused only brief laryngospasm with full recovery. Pre-treatment with naloxone (1 mg/kg) prevented fentanyl-induced VCC, but naloxone (1 and 2 mg/kg) was unable to reverse VCC when administered after fentanyl. CONCLUSIONS: These results indicate sustained VCC is a lethal physiological reaction, specific to fentanyl and resistant to naloxone treatment. While pre-treatment with naloxone prevented fentanyl-induced VCC, naloxone was unable to reverse the effect, suggesting a non-opioid receptor-mediated mechanism. These findings demonstrate the necessity of VCC inclusion in animal models of synthetic opioid overdose and the urgent need for more effective treatments for fentanyl-related overdoses.


Assuntos
Overdose de Drogas , Overdose de Opiáceos , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Animais , Overdose de Drogas/tratamento farmacológico , Fentanila/efeitos adversos , Fentanila/uso terapêutico , Naloxona/farmacologia , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu , Prega Vocal
3.
Molecules ; 26(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34361663

RESUMO

Opioid-associated overdoses and deaths due to respiratory depression are a major public health problem in the US and other Western countries. In the past decade, much research effort has been directed towards the development of G-protein-biased µ-opioid receptor (MOP) agonists as a possible means to circumvent this problem. The bias hypothesis proposes that G-protein signaling mediates analgesia, whereas ß-arrestin signaling mediates respiratory depression. SR-17018 was initially reported as a highly biased µ-opioid with an extremely wide therapeutic window. It was later shown that SR-17018 can also reverse morphine tolerance and prevent withdrawal via a hitherto unknown mechanism of action. Here, we examined the temporal dynamics of SR-17018-induced MOP phosphorylation and dephosphorylation. Exposure of MOP to saturating concentrations of SR-17018 for extended periods of time stimulated a MOP phosphorylation pattern that was indistinguishable from that induced by the full agonist DAMGO. Unlike DAMGO-induced MOP phosphorylation, which is reversible within minutes after agonist washout, SR-17018-induced MOP phosphorylation persisted for hours under otherwise identical conditions. Such delayed MOP dephosphorylation kinetics were also found for the partial agonist buprenorphine. However, buprenorphine, SR-17018-induced MOP phosphorylation was fully reversible when naloxone was included in the washout solution. SR-17018 exhibits a qualitative and temporal MOP phosphorylation profile that is strikingly different from any other known biased, partial, or full MOP agonist. We conclude that detailed analysis of receptor phosphorylation may provide novel insights into previously unappreciated pharmacological properties of newly synthesized MOP ligands.


Assuntos
Analgésicos Opioides/farmacologia , Buprenorfina/farmacologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Analgésicos Opioides/química , Buprenorfina/química , Tolerância a Medicamentos , Ala(2)-MePhe(4)-Gly(5)-Encefalina/química , Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Ligantes , Estrutura Molecular , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Overdose de Opiáceos/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transfecção , beta-Arrestina 2/metabolismo
4.
Psychopharmacology (Berl) ; 238(11): 3183-3191, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34333672

RESUMO

RATIONALE: Kratom (Mitragyna speciosa Korth), a native medicinal plant of Southeast Asia, is proposed to exhibit potential therapeutic value as an opioid substitute. However, studies of its negative emotional states resulting from withdrawal particularly of its main psychoactive compound, mitragynine (MG), are limited. OBJECTIVES: Using the pentylenetetrazol (PTZ) discrimination assay, this study aims to investigate the effects of MG in responding to the PTZ stimulus and to assess the generalisation effects of withdrawal from MG to the PTZ stimulus. METHODS: Rats (n = 20) were trained on a tandem (FR-10, VI-15) schedule of food reinforcement to press one lever after administration of the anxiogenic compound PTZ (16 mg/kg, i.p.) and an alternate lever after vehicle. Following acute tests, training was suspended, and rats were chronically treated with MG or morphine at 8-h intervals for 9 days and withdrawal was precipitated on the tenth day using naloxone (1 mg/kg, i.p.). The rats were tested for generalisation to PTZ at 2, 8 and 24 h after the last dose of MG or morphine administration. RESULTS: Unlike morphine that produced dose-related PTZ-like stimulus, MG at 3, 10, 30 and 45 mg/kg doses showed no substitution to the PTZ discriminative stimulus. In contrast to morphine which produced a time-dependent generalisation to the PTZ stimulus, naloxone did not precipitate withdrawal effects in MG-treated rats as they selected the vehicle lever at three withdrawal time points. CONCLUSION: These results demonstrate that MG produces a very different response to morphine withdrawal that is not associated with anxiogenic-like subjective symptoms. These characteristics of MG may provide further support for use as a novel pharmacotherapeutic intervention for managing opioid use disorder.


Assuntos
Alcaloides de Triptamina e Secologanina , Síndrome de Abstinência a Substâncias , Animais , Naloxona/farmacologia , Pentilenotetrazol , Ratos , Alcaloides de Triptamina e Secologanina/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico
5.
Comput Math Methods Med ; 2021: 7731528, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373698

RESUMO

Aim: The aim of this study was to evaluate the anti-inflammatory effects and underlying mechanism of naloxone on lipopolysaccharide- (LPS-) induced neuronal inflammation and microglial activation. Methods: LPS-treated microglial BV-2 cells and mice were used to investigate the anti-inflammatory effects of naloxone. Results: The results showed that naloxone dose-dependently promoted cell proliferation in LPS-induced BV-2 cells, downregulated the expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) and proinflammatory enzymes iNOS and COX-2 as well as the expression of free radical molecule NO, and reduced the expression of Iba-1-positive microglia in LPS-stimulated BV-2 cells and mouse brain. Moreover, naloxone improved LPS-induced behavior degeneration in mice. Mechanically, naloxone inhibited LPS-induced activation in the ATP-sensitive potassium (KATP) channel. However, the presence of glibenclamide (Glib), an antagonist of KATP channel, ameliorated the suppressive effects of naloxone on inflammation and microglial activation. Conclusion: Naloxone prevented LPS-induced neuroinflammation and microglial activation partially through the KATP channel. These findings might highlight the potential of naloxone in neuroinflammation therapy.


Assuntos
Inflamação/prevenção & controle , Canais KATP/antagonistas & inibidores , Microglia/efeitos dos fármacos , Naloxona/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Biologia Computacional , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Microglia/metabolismo , Microglia/patologia , Antagonistas de Entorpecentes/farmacologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/prevenção & controle
6.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199486

RESUMO

In this study, we aimed to design and synthesize novel molecules carrying both the thiazole and piperazine rings in their structures and to investigate their antinociceptive activity. Targeted compounds were obtained by reacting thiosemicarbazide derivative and appropriate 2-bromoacetophenone in ethanol. The structures of the obtained compounds were determined using data from various spectroscopic methods (IR, 1H-NMR, 13C-NMR, and LCMSMS). Experimental data from in vivo tests showed that test compounds 3a-3c, 3f, and 3g (50 mg/kg) significantly prolonged reaction times of animals in tail-clip and hot-plate tests compared to the controls, indicating that these compounds possess centrally mediated antinociceptive activities. Furthermore, these compounds reduced the number of writhing behaviors in the acetic acid-induced writhing tests, showing that the compounds also possess peripheral antinociceptive activity. In the mechanistic studies, naloxone pre-treatments abolished the antinociceptive activities of compounds 3a-3c, 3f, and 3g, indicating that opioidergic mechanisms were involved in their antinociceptive effects. Molecular docking studies demonstrating significant interactions between the active compounds and µ- and δ-opioid receptor proteins supported the pharmacological findings. This study is the first showing that molecules designed to bear thiazole and piperazine moieties together on their structure exert centrally and peripherally mediated antinociceptive effects by activating the opioid system.


Assuntos
Acetofenonas/química , Analgésicos/administração & dosagem , Analgésicos/síntese química , Dor/tratamento farmacológico , Receptores Opioides/metabolismo , Semicarbazidas/química , Analgésicos/química , Analgésicos/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Naloxona/administração & dosagem , Naloxona/farmacologia , Dor/metabolismo , Conformação Proteica , Receptores Opioides/química , Receptores Opioides delta/química , Receptores Opioides delta/metabolismo , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo
7.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299013

RESUMO

Mucosal CD4+ T lymphocytes display a potent opioid-mediated analgesic activity in interleukin (IL)-10 knockout mouse model of inflammatory bowel diseases (IBD). Considering that endogenous opioids may also exhibit anti-inflammatory activities in the periphery, we examined the consequences of a peripheral opioid receptor blockade by naloxone-methiodide, a general opioid receptor antagonist unable to cross the blood-brain barrier, on the development of piroxicam-accelerated colitis in IL-10-deficient (IL-10-/-) mice. Here, we show that IL-10-deficient mice treated with piroxicam exhibited significant alterations of the intestinal barrier function, including permeability, inflammation-related bioactive lipid mediators, and mucosal CD4+ T lymphocyte subsets. Opioid receptor antagonization in the periphery had virtually no effect on colitis severity but significantly worsened epithelial cell apoptosis and intestinal permeability. Thus, although the endogenous opioid tone is not sufficient to reduce the severity of colitis significantly, it substantially contributes to the protection of the physical integrity of the epithelial barrier.


Assuntos
Colite/metabolismo , Interleucina-10/genética , Mucosa Intestinal/efeitos dos fármacos , Naloxona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Piroxicam/farmacologia , Receptores Opioides/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Citocinas/genética , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/metabolismo , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naloxona/farmacologia , Permeabilidade/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Índice de Gravidade de Doença
8.
Molecules ; 26(11)2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071603

RESUMO

Opioids are the most effective analgesics, with most clinically available opioids being agonists to the µ-opioid receptor (MOR). The MOR is also responsible for their unwanted effects, including reward and opioid misuse leading to the current public health crisis. The imperative need for safer, non-addictive pain therapies drives the search for novel leads and new treatment strategies. In this study, the recently discovered MOR/nociceptin (NOP) receptor peptide hybrid KGNOP1 (H-Dmt-D-Arg-Aba-ß-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) was evaluated following subcutaneous administration in mouse models of acute (formalin test) and chronic inflammatory pain (Complete Freund's adjuvant-induced paw hyperalgesia), liabilities of spontaneous locomotion, conditioned place preference, and the withdrawal syndrome. KGNOP1 demonstrated dose-dependent antinociceptive effects in the formalin test, and efficacy in attenuating thermal hyperalgesia with prolonged duration of action. Antinociceptive effects of KGNOP1 were reversed by naltrexone and SB-612111, indicating the involvement of both MOR and NOP receptor agonism. In comparison with morphine, KGNOP1 was more potent and effective in mouse models of inflammatory pain. Unlike morphine, KGNOP1 displayed reduced detrimental liabilities, as no locomotor impairment nor rewarding and withdrawal effects were observed. Docking of KGNOP1 to the MOR and NOP receptors and subsequent 3D interaction pattern analyses provided valuable insights into its binding mode. The mixed MOR/NOP receptor peptide KGNOP1 holds promise in the effort to develop new analgesics for the treatment of various pain states with fewer MOR-mediated side effects, particularly abuse and dependence liabilities.


Assuntos
Oligopeptídeos/genética , Peptídeos Opioides/química , Receptores Opioides mu/metabolismo , Dor Aguda/tratamento farmacológico , Analgésicos , Animais , Comportamento Animal , Células CHO , Cricetinae , Cricetulus , Cicloeptanos/farmacologia , Humanos , Hiperalgesia/tratamento farmacológico , Técnicas In Vitro , Inflamação/tratamento farmacológico , Masculino , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Morfina/química , Morfina/farmacologia , Movimento/efeitos dos fármacos , Naloxona/farmacologia , Naltrexona/farmacologia , Manejo da Dor , Piperidinas/farmacologia
9.
Biomed Pharmacother ; 139: 111649, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33957565

RESUMO

Visceral hypersensitivity and impaired gut barrier are crucial contributors to the pathophysiology of irritable bowel syndrome (IBS), and those are mediated via corticotropin-releasing factor (CRF)-Toll like receptor 4-pro-inflammatory cytokine signaling. Phlorizin is an inhibitor of sodium-linked glucose transporters (SGLTs), and known to have anti-cytokine properties. Thus, we hypothesized that phlorizin may improve these gastrointestinal changes in IBS, and tested this hypothesis in rat IBS models, i.e., lipopolysaccharide (LPS) or CRF-induced visceral hypersensitivity and colonic hyperpermeability. The visceral pain threshold in response to colonic balloon distention was estimated by abdominal muscle contractions by electromyogram, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue. Subcutaneous (s.c.) injection of phlorizin inhibited visceral hypersensitivity and colonic hyperpermeability induced by LPS in a dose-dependent manner. Phlorizin also blocked CRF-induced these gastrointestinal changes. Phlorizin is known to inhibit both SGLT1 and SGLT2, but intragastric administration of phlorizin may only inhibit SGLT1 because gut mainly expresses SGLT1. We found that intragastric phlorizin did not display any effects, but ipragliflozin, an orally active and selective SGLT2 inhibitor improved the gastrointestinal changes in the LPS model. Compound C, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor and naloxone, an opioid receptor antagonist reversed the effects of phlorizin. In conclusions, phlorizin improved visceral hypersensitivity and colonic hyperpermeability in IBS models. These effects may result from inhibition of SGLT2, and were mediated via AMPK, NO and opioid pathways. Phlorizin may be effective for the treatment of IBS.


Assuntos
Colo/metabolismo , Hiperalgesia/tratamento farmacológico , Síndrome do Intestino Irritável/tratamento farmacológico , Florizina/uso terapêutico , Músculos Abdominais/efeitos dos fármacos , Animais , Colo/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Relação Dose-Resposta a Droga , Eletromiografia , Injeções Subcutâneas , Lipopolissacarídeos/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Naloxona/farmacologia , Permeabilidade , Florizina/antagonistas & inibidores , Florizina/farmacologia , Ratos , Ratos Sprague-Dawley
10.
Eur J Pharmacol ; 903: 174132, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33933466

RESUMO

Opioid-induced constipation is the most prevalent adverse effect of opioid drugs. Peripherally acting mu opioid receptor antagonists (PAMORAs), including naloxegol, are indicated for the treatment of opioid-induced constipation. The aim of this study was the in vitro and in vivo pharmacological characterization of naloxegol in comparison with naloxone. In vitro experiments were performed to measure calcium mobilization in cells coexpressing opioid receptors and chimeric G proteins and mu receptor interaction with G protein and ß-arrestin 2 using bioluminescence resonance energy transfer. In vivo experiments were performed in mice to measure pain threshold using the tail withdrawal assay and colonic transit using the bead expulsion assay. In vitro, naloxegol behaved as a selective and competitive mu receptor antagonist similarly to naloxone, being 3-10-fold less potent. In vivo, naloxone was effective in blocking fentanyl actions when given subcutaneously (sc), but not per os (po). In contrast, naloxegol elicited very similar effects with sc or po administration counteracting in a dose dependent manner the constipating effects of fentanyl without interfering with the fentanyl mediated analgesia. Thus, a useful PAMORA action could be obtained with naloxegol both after po and sc administration.


Assuntos
Constipação Intestinal/tratamento farmacológico , Morfinanos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Polietilenoglicóis/farmacologia , Administração Oral , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Células CHO , Cálcio/metabolismo , Constipação Intestinal/induzido quimicamente , Cricetulus , Fentanila/administração & dosagem , Fentanila/efeitos adversos , Fentanila/farmacologia , Injeções Subcutâneas , Masculino , Camundongos , Morfinanos/administração & dosagem , Morfina/farmacologia , Naloxona/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Dor/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/efeitos dos fármacos
11.
eNeuro ; 8(3)2021.
Artigo em Inglês | MEDLINE | ID: mdl-33903183

RESUMO

Neuropeptides are implicated in control of lateralized processes in the brain. A unilateral brain injury (UBI) causes the contralesional sensorimotor deficits. To examine whether opioid neuropeptides mediate UBI induced asymmetric processes we compared effects of opioid antagonists on the contralesional and ipsilesional hindlimb responses to the left-sided and right-sided injury in rats. UBI induced hindlimb postural asymmetry (HL-PA) with the contralesional hindlimb flexion, and activated contralesional withdrawal reflex of extensor digitorum longus (EDL) evoked by electrical stimulation and recorded with EMG technique. No effects on the interossei (Int) and peroneaus longus (PL) were evident. The general opioid antagonist naloxone blocked postural effects, did not change EDL asymmetry while uncovered cryptic asymmetry in the PL and Int reflexes induced by UBI. Thus, the spinal opioid system may either mediate or counteract the injury effects. Strikingly, effects of selective opioid antagonists were the injury side-specific. The µ-antagonist ß-funaltrexamine (FNA) and κ-antagonist nor-binaltorphimine (BNI) reduced postural asymmetry after the right but not left UBI. In contrast, the δ-antagonist naltrindole (NTI) inhibited HL-PA after the left but not right-side brain injury. The opioid gene expression and opioid peptides were lateralized in the lumbar spinal cord, and coordination between expression of the opioid and neuroplasticity-related genes was impaired by UBI that together may underlie the side-specific effects of the antagonists. We suggest that mirror-symmetric neural circuits that mediate effects of left and right brain injury on the contralesional hindlimbs are differentially controlled by the lateralized opioid system.


Assuntos
Lesões Encefálicas , Neuropeptídeos , Animais , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos , Receptores Opioides mu , Medula Espinal
12.
Biomolecules ; 11(4)2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920609

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
13.
Eur J Pharmacol ; 903: 174111, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33901461

RESUMO

Opioid use disorder is a growing concern in the United States. Mice were used to investigate the mechanisms involving opioid physical dependence and for evaluating medications for treating opioid use disorders. While there are many preclinical reports describing protocols for inducing physical dependence upon morphine, there are fewer preclinical reports describing more contemporary abused prescription opiates. The goal of this study was to characterize and validate a mouse model of oxycodone dependence. Male C57BL/6J mice were injected with saline or increasing doses of oxycodone (9-33 mg/kg) twice daily for 8 days. On the 9th day, mice were challenged with 1 mg/kg naloxone and observed for somatic signs. Mice were pretreated with oxycodone (17, 33, or 75 mg/kg) prior to withdrawal to determine if it could attenuate somatic withdrawal signs. Additional mouse groups were pretreated with 1 mg/kg clonidine. Lastly, we measured somatic signs for 6, 24, and 48 h post-withdrawal during spontaneous and precipitated withdrawal. Pretreating with oxycodone or clonidine dose-dependently prevented the emergence of withdrawal signs. Mice chronically treated with oxycodone exhibited more withdrawal signs than vehicle at 24 h after the final injection during spontaneous withdrawal. In contrast, mice that received repeated naloxone challenges showed peak withdrawal signs at 6 h, and withdrawal signs were significantly greater at all time points compared to vehicle. Reversal of withdrawal effects by positive controls, and establishing spontaneous and precipitated withdrawal paradigms, serve as validation of this model and provide a means to examine novel therapeutics to treat opioid withdrawal.


Assuntos
Analgésicos Opioides/farmacologia , Transtornos Relacionados ao Uso de Opioides/etiologia , Oxicodona/farmacologia , Síndrome de Abstinência a Substâncias/etiologia , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Clonidina/administração & dosagem , Clonidina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos Endogâmicos C57BL , Naloxona/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Síndrome de Abstinência a Substâncias/prevenção & controle
14.
Int J Mol Sci ; 22(8)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920718

RESUMO

The opioid system is well-known for its role in modulating nociception and addiction development. However, there are premises that the endogenous opioid system may also affect blood pressure. The main goal of the present study was to determine the impact of different endogenous opioid system activity and its pharmacological blockade on blood pressure. Moreover, we examined the vascular function in hyper- and hypoactive states of the opioid system and its pharmacological modification. In our study, we used two mouse lines which are divergently bred for high (HA) and low (LA) swim stress-induced analgesia. The obtained results indicated that individuals with low endogenous opioid system activity have higher basal blood pressure compared to those with a hyperactive opioid system. Additionally, naloxone administration only resulted in the elevation of blood pressure in HA mice. We also showed that the hypoactive opioid system contributes to impaired vascular relaxation independent of endothelium, which corresponded with decreased guanylyl cyclase levels in the aorta. Together, these data suggest that higher basal blood pressure in LA mice is a result of disturbed mechanisms in vascular relaxation in smooth muscle cells. We believe that a novel mechanism which involves endogenous opioid system activity in the regulation of blood pressure will be a promising target for further studies in hypertension development.


Assuntos
Aorta/efeitos dos fármacos , Pressão Sanguínea , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Nociceptividade , Animais , Aorta/citologia , Aorta/metabolismo , Endotélio Vascular/efeitos dos fármacos , Feminino , Guanilato Ciclase/metabolismo , Masculino , Camundongos , Miócitos de Músculo Liso/efeitos dos fármacos , Vasodilatação
15.
Eur J Pharmacol ; 901: 174089, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33826922

RESUMO

The participation of the peripheral opioid and cannabinoid endogenous systems in modulating muscle pain and inflammation has not been fully explored. Thus, the aim of this study was to investigate the involvement of these endogenous systems during muscular-tissue hyperalgesia induced by inflammation. Hyperalgesia was induced by carrageenan injection into the tibialis anterior muscles of male Wistar rats. We padronized an available Randal-Sellito test adaptation to evaluate nociceptive behavior elicited by mechanical insult in muscles. Western blot analysis was performed to evaluate the expression levels of opioid and cannabinoid receptors in the dorsal root ganglia. The non-selective opioid peptide receptor antagonist (naloxone) and the selective mu opioid receptor MOP (clocinnamox) and kappa opioid receptor KOP (nor-binaltorphimine) antagonists were able to intensify carrageenan-induced muscular hyperalgesia. On the other hand, the selective delta opioid receptor (DOP) antagonist (naltrindole) did not present any effect on nociceptive behavior. Moreover, the selective inhibitor of aminopeptidases (Bestatin) provoked considerable dose-dependent analgesia when intramuscularly injected into the hyperalgesic muscle. The CB1 receptor antagonist (AM251), but not the CB2 receptor antagonist (AM630), intensified muscle hyperalgesia. All irreversible inhibitors of anandamide hydrolase (MAFP), the inhibitor for monoacylglycerol lipase (JZL184) and the anandamide reuptake inhibitor (VDM11) decreased carrageenan-induced hyperalgesia in muscular tissue. Lastly, MOP, KOP and CB1 expression levels in DRG were baseline even after muscular injection with carrageenan. The endogenous opioid and cannabinoid systems participate in peripheral muscle pain control through the activation of MOP, KOP and CB1 receptors.


Assuntos
Mialgia/tratamento farmacológico , Receptores de Canabinoides/fisiologia , Receptores Opioides/fisiologia , Animais , Ácidos Araquidônicos/antagonistas & inibidores , Carragenina , Cinamatos/farmacologia , Endocanabinoides/antagonistas & inibidores , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/psicologia , Masculino , Monoacilglicerol Lipases/antagonistas & inibidores , Derivados da Morfina/farmacologia , Mialgia/induzido quimicamente , Mialgia/psicologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Medição da Dor/efeitos dos fármacos , Alcamidas Poli-Insaturadas/antagonistas & inibidores , Ratos , Ratos Wistar , Receptores de Canabinoides/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Receptores Opioides delta/efeitos dos fármacos , Receptores Opioides kappa/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos
16.
Chem Biol Interact ; 342: 109475, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33872574

RESUMO

Endorphins are endogenous opioid neuropeptides that are mainly produced from pituitary gland in response to pain and different triggers including interleukin 1 beta (IL-1ß) and corticotropin-releasing factor (CRF). Angiotensin II (Ang II) can stimulate ß-endorphin production, but the exact molecular mechanisms involved in this effect, and the role of the released ß-endorphin in Ang II-mediated pressor response remain elusive. Male rats were injected with IL-1ß receptor antagonist (IL-1Ra, 100 µg/kg), the CRF receptor blocker, astressin (20 µg/rat) or a combination of both, prior to Ang II injection (200 µg/kg). Another group of rats was given naloxone (1.6 mg/kg) or telmisartan (5 mg/kg) before Ang II injection. Blood pressure and serum and Paraventricular nucleus (PVN) ß-endorphin were detected. Moreover, IL-1ß and CRF as well as markers of oxidative stress [malondialdehyde (MDA) and superoxide dismutase (SOD)], inflammation [C-reactive protein (CRP)] and neuronal activation (c-Fos, l-glutamate, and phosphorylated ERK) were measured in the PVN of different groups. Ang II induced a pressor response and increased serum and PVN ß-endorphin levels that were attenuated in rats pre-treated with astressin or/and IL-1Ra. Moreover, Ang II increased PVN oxidative stress, inflammation and neuronal activation. Telmisartan abolished the previous effects, while naloxone, astressin and IL-1Ra aggravated Ang II-mediated pressor response and most of the biochemical changes. These findings suggest that, Ang II can induce ß-endorphin release via increasing both IL-1ß and CRF levels which in result mitigates Ang II-mediated central responses. This study highlights ß-endorphin as a possible target for treating hypertension.


Assuntos
Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , beta-Endorfina/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/metabolismo , Masculino , Naloxona/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Fragmentos de Peptídeos/farmacologia , Ratos , Telmisartan/farmacologia
17.
Pain Res Manag ; 2021: 6639009, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33603939

RESUMO

Femoral nerve blocks (FNBs) are used as safe and useful procedures to control severe postoperative pain from total knee arthroplasty (TKA). Various adjuvants have been used to prolong the duration of the local anesthetic blockade. This study evaluated whether a low dose of naloxone administered with local anesthetics prolongs the duration of FNB. A prospective, randomized double-blind controlled study was conducted with 74 patients undergoing unilateral TKA. Through a single-bolus administration guided by ultrasound, the control group (group C) received 20 mL of 0.375% ropivacaine, while the naloxone group (group N) received 20 mL of 0.375% ropivacaine with 100 ng of naloxone. The time elapsed before the first analgesia request, the total amount of opioids consumed at 24 h postoperatively, the onset time of the sensory blockade, the visual analog pain scale (VAS) scores after arriving at the recovery room, after 6, 12, 18, and 24 h at rest and after 12, 18, and 24 h of activity, the quadricep strength before the FNB procedure and at 12 and 24 h postoperatively, the quality of sleep on the first night after surgery, the satisfaction score, and the incidence of postoperative complications were recorded. The time elapsed before the first analgesia request was significantly longer in group N (735.5 ± 187.2 min) than that in group C (602.6 ± 210.4 min) (P=0.003). The total dose of supplementary opioids consumed at 24 h postoperatively was significantly lower in group N (312.4 ± 141.7 µg) than that in group C (456.5 ± 279.5 µg) (P=0.007). Lower VAS scores were recorded in group N than that in group C at rest and during knee activity (rest, 12 h, P=0.001, 18 h, P=0.043; activity, 12 h, P=0.001). The addition of a low dose of naloxone to ropivacaine for FNB significantly delayed the first request for rescue analgesia and decreased the opioid consumption within 24 h, without significant complications.


Assuntos
Nervo Femoral/efeitos dos fármacos , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Bloqueio Nervoso/métodos , Ropivacaina/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Estudos Prospectivos , Ropivacaina/farmacologia
18.
Mar Drugs ; 19(1)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33478061

RESUMO

N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a conantokin-T variant) that potently inhibits the naloxone-induced jumping and conditioned place preference of morphine-dependent mice at nmol/kg level, 100-fold higher than ifenprodil, a classical NMDAR NR2B antagonist. Con-T[M8Q] displays no significant impacts on coordinated locomotion function, spontaneous locomotor activity, and spatial memory mice motor function at the dose used. Further molecular mechanism experiments demonstrate that con-T[M8Q] effectively inhibited the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in hippocampus, including NR2B, p-NR2B, CaMKII-α, CaMKII-ß, CaMKIV, pERK, and c-fos. The high efficacy and low side effects of con-T[M8Q] make it a good lead compound for the treatment of opiate dependence and for the reduction of morphine usage.


Assuntos
Conotoxinas/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Dependência de Morfina/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Animais , Conotoxinas/administração & dosagem , Conotoxinas/toxicidade , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Dependência de Morfina/fisiopatologia , Naloxona/farmacologia , Piperidinas/farmacologia , Memória Espacial/efeitos dos fármacos
19.
Ann Neurol ; 89(2): 199-211, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33159466

RESUMO

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin-associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach originally developed for cancer called "transcriptome reversal" for these neurodevelopmental disorders. This approach attempts to identify compounds that reverse gene-expression signatures associated with disease states. ANN NEUROL 2021;89:199-211.


Assuntos
Regulação da Expressão Gênica/genética , Células-Tronco Neurais/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Neurônios/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anticonvulsivantes/farmacologia , Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Carbamazepina/farmacologia , Simulação por Computador , Descoberta de Drogas , Epirizol/farmacologia , Perfilação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas , Células MCF-7 , Camundongos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Células-Tronco Neurais/metabolismo , Transtornos do Neurodesenvolvimento/genética , Neurônios/metabolismo , Células PC-3 , Perfenazina/farmacologia , Cultura Primária de Células , RNA-Seq , Risperidona/farmacologia , Análise de Célula Única , Trazodona/farmacologia , Trimipramina/farmacologia
20.
Life Sci ; 265: 118836, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33259865

RESUMO

AIMS: Our previous study has demonstrated that porcine diazepam-binding inhibitor (pDBI) and its active fragments, pDBI-16 and pDBI-19, have inhibition effect on morphine analgesia in mice. The present study aimed to investigate the underlying mechanism and potential application of this anti-opioid effect. MATERIALS AND METHODS: Effect of DBI on morphine analgesia was examined by the tail electric stimulation vocalization test. Complementary peptides and antiserum were used to further confirm the effect of DBI in morphine tolerance and dependence. Pharmacological and microinjection methods were used to investigate the underlying mechanism. KEY FINDINGS: Firstly, pDBI administered either intracerebroventricularly or intravenously dose-dependently inhibited morphine analgesia, while blocking DBI-16 or DBI-19 by the complementary peptides for DBI-16 (CP-DBI-16) or DBI-19 (CP-DBI-19) potentiated it in mice. Secondly, explicit immunoexpression of DBI in the lateral habenular (LHb) was observed in naive rats, and intra-LHb injection of pDBI dose-dependently abolished analgesic effect produced by intra-periaqueductal gray (PAG) injection of morphine in rats. Thirdly, pretreatment with N-Methyl-d-Aspartate receptor (NMDAR) antagonist MK-801 or nitric oxide (NO) synthase inhibitor L-NAME abolished the inhibition effect of pDBI, pDBI-16 or pDBI-19 on morphine analgesia in mice. Finally, antiserum against DBI dose-dependently reversed analgesic tolerance induced by increasing doses of morphine twice daily for 13 days in mice, while CP-DBI-16 or CP-DBI-19 significantly inhibited naloxone-precipitated morphine withdrawal jumping in mice. SIGNIFICANCE: Taken together, our results demonstrated that NMDAR/NO signaling and LHb-PAG pathway are crucially involved in the anti-opioid effect of DBI, which could provide a potential biological target for opioid tolerance and dependence.


Assuntos
Analgésicos Opioides/farmacologia , Inibidor da Ligação a Diazepam/farmacologia , Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Analgésicos Opioides/administração & dosagem , Animais , Inibidor da Ligação a Diazepam/administração & dosagem , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Estimulação Elétrica , Masculino , Camundongos , Morfina/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Óxido Nítrico/metabolismo , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Suínos , Cauda , Vocalização Animal/efeitos dos fármacos
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