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1.
Int J Mol Sci ; 25(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38473865

RESUMO

Opioid peptides and their G protein-coupled receptors are important regulators within the cardiovascular system, implicated in the modulation of both heart and vascular functions. It is known that naloxone-an opioid antagonist-may exert a hypertensive effect. Recent experimental and clinical evidence supports the important role of inflammatory mechanisms in hypertension. Since opioids may play a role in the regulation of both blood pressure and immune response, we studied these two processes in our model. We aimed to evaluate the effect of selective and non-selective opioid receptor antagonists on blood pressure and T-cell activation in a mouse model of high swim stress-induced analgesia. Blood pressure was measured before and during the infusion of opioid receptor antagonists using a non-invasive tail-cuff measurement system. To assess the activation of T-cells, flow cytometry was used. We discovered that the non-selective antagonism of the opioid system by naloxone caused a significant elevation of blood pressure. The selective antagonism of µ and κ but not δ opioid receptors significantly increased systolic blood pressure. Subsequently, a brief characterization of T-cell subsets was performed. We found that the blockade of µ and δ receptors is associated with the increased expression of CD69 on CD4 T-cells. Moreover, we observed an increase in the central memory CD4 and central memory CD8 T-cell populations after the δ opioid receptor blockade. The antagonism of the µ opioid receptor increased the CD8 effector and central memory T-cell populations.


Assuntos
Analgesia , Hipertensão , Camundongos , Animais , Antagonistas de Entorpecentes/farmacologia , Pressão Sanguínea , Receptores Opioides delta/metabolismo , Naloxona/farmacologia , Receptores Opioides mu , Dor , Analgésicos Opioides/farmacologia , Receptores Opioides kappa/metabolismo
2.
Bull Exp Biol Med ; 176(3): 338-341, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38340196

RESUMO

A comparative analysis of the infarct-limiting activity of δ- and κ-opioid receptors (OR) agonists was carried out on a model of coronary occlusion (45 min) and reperfusion (120 min) in male Wistar rats. We used selective δ2-OR agonist deltorphin II (0.12 mg/kg), δ-OR agonists BW373U86 and p-Cl-Phe DPDPE (0.1 and 1 mg/kg), selective agonists of δ1-OR DPDPE (0.1 and 0.969 mg/kg), κ1-OR U-50,488 (0.1 and 1 mg/kg), κ2-OR GR-89696 (0.1 mg/kg), and κ-OR ICI-199,441 (0.1 mg/kg). All drugs were administered intravenously 5 min before reperfusion. Deltorphin II, BW373U86 (1 mg/kg), p-Cl-Phe DPDPE (1 mg/kg), U-50,488 (1 mg/kg), and ICI-199,441 had a cardioprotective effect. The most promising compounds for drug development are ICI-199,441 and deltorphin II.


Assuntos
Benzamidas , Reperfusão Miocárdica , Piperazinas , Receptores Opioides delta , Ratos , Animais , Masculino , Ratos Wistar , D-Penicilina (2,5)-Encefalina , Infarto
3.
Mol Pharm ; 21(2): 688-703, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38243899

RESUMO

Persistent pain is a significant healthcare problem with limited treatment options. The high incidence of comorbid chronic pain and depression significantly reduces life quality and complicates the treatment of both conditions. Antidepressants are less effective for pain and depression than for depression alone and they induce severe side effects. Opioids are highly efficacious analgesics, but rapid development of tolerance, dependence, and debilitating side effects limit their efficacy and safe use. Leucine-enkephalin (Leu-ENK), the endogenous delta opioid receptor agonist, controls pain and mood and produces potent analgesia with reduced adverse effects compared to conventional opioids. High proteolytic instability, however, makes Leu-ENK ineffective after systemic administration and limits its clinical usefulness. KK-103, a Leu-ENK prodrug, was developed to overcome these limitations of Leu-ENK via markedly increased plasma stability in mice. We showed rapid and substantially increased systemic adsorption and blood plasma exposure of KK-103 compared to Leu-ENK. We also observed brain uptake of radiolabeled KK-103 after systemic administration, indicating a central effect of KK-103. We then established KK-103's prolonged antinociceptive efficacy in the ramped hot plate and formalin test. In both models, KK-103 produced a comparable dose to the maximum antinociceptive-effect relationship. The pain-alleviating effect of KK-103 primarily resulted from activating the delta opioid receptor after the likely conversion of KK-103 to Leu-ENK in vivo. Finally, KK-103 produced an antidepressant-like activity comparable to the antidepressant desipramine, but with minimal gastrointestinal inhibition and no incidence of sedation.


Assuntos
Encefalina Leucina , Pró-Fármacos , Camundongos , Animais , Receptores Opioides delta/uso terapêutico , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Dor/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico
4.
Br J Pharmacol ; 181(5): 712-734, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37766498

RESUMO

BACKGROUND AND PURPOSE: Autophagy is a protective factor for controlling neuronal damage, while necroptosis promotes neuroinflammation after spinal cord injury (SCI). DADLE (D-Ala2 , D-Leu5 ]-enkephalin) is a selective agonist for delta (δ) opioid receptor and has been identified as a promising drug for neuroprotection. The aim of this study was to investigate the mechanism/s by which DADLE causes locomotor recovery following SCI. EXPERIMENTAL APPROACH: Spinal cord contusion model was used and DADLE was given by i.p. (16 mg·kg-1 ) in mice for following experiments. Motor function was assessed by footprint and Basso mouse scale (BMS) score analysis. Western blotting used to evaluate related protein expression. Immunofluorescence showed the protein expression in each cell and its distribution. Network pharmacology analysis was used to find the related signalling pathways. KEY RESULTS: DADLE promoted functional recovery after SCI. In SCI model of mice, DADLE significantly increased autophagic flux and inhibited necroptosis. Concurrently, DADLE restored autophagic flux by decreasing lysosomal membrane permeabilization (LMP). Additionally, chloroquine administration reversed the protective effect of DADLE to inhibit necroptosis. Further analysis showed that DADLE decreased phosphorylated cPLA2 , overexpression of cPLA2 partially reversed DADLE inhibitory effect on LMP and necroptosis, as well as the promotion autophagy. Finally, AMPK/SIRT1/p38 pathway regulating cPLA2 is involved in the action DADLE on SCI and naltrindole inhibited DADLE action on δ receptor and on AMPK signalling pathway. CONCLUSION AND IMPLICATION: DADLE causes its neuroprotective effects on SCI by promoting autophagic flux and inhibiting necroptosis by decreasing LMP via activating δ receptor/AMPK/SIRT1/p38/cPLA2 pathway.


Assuntos
Leucina Encefalina-2-Alanina , Traumatismos da Medula Espinal , Animais , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Leucina Encefalina-2-Alanina/metabolismo , Leucina Encefalina-2-Alanina/farmacologia , Lisossomos/metabolismo , Fosfolipases/metabolismo , Receptores Opioides delta/metabolismo , Recuperação de Função Fisiológica , Sirtuína 1/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo
5.
Neuropsychopharmacol Rep ; 44(1): 256-261, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38156409

RESUMO

AIM: Excitatory projections from the prelimbic cortex (PL) to the basolateral nucleus of the amygdala (BLA) are implicated in the regulation of anxiety-like behaviors, and we previously demonstrated that anxiolytic-like effects of the selective delta-opioid receptor (DOP) agonist KNT-127 is involved in suppressing glutamate neurotransmission in the PL. Here, we investigated the mechanisms underlying the anxiolytic-like effect of KNT-127 in mice by combining optogenetic stimulation of the PL-BLA pathway with behavioral analyses. METHODS: Four-week-old male C57BL/6J mice received bilateral administration of adeno-associated virus (AAV)2-CaMKIIa-hChR2(H134R)-enhanced yellow fluorescent protein (EYFP) into the PL to induce expression of the light-activated excitatory ionic channel ChR2. Subsequently, an optic fiber cannula connected to a wireless photo-stimulator was implanted into the BLA for optogenetic PL-BLA pathway stimulation. We evaluated innate anxiety using the elevated plus maze (EPM) and open field (OF) tests as well as learned anxiety using the contextual fear conditioning (CFC) test. RESULTS: Optogenetic activation of the PL-BLA pathway enhanced anxiety-like behaviors in the EPM and OF, while prior subcutaneous administration of KNT-127 (10 mg/kg) reduced this anxiogenic effect. In contrast, optogenetic activation of the PL-BLA pathway had no significant effect on conditioned fear. CONCLUSION: Our findings indicate that the PL-BLA circuit contributes to innate anxiety and that the anxiolytic-like effects of KNT-127 are mediated at least in part by suppression of PL-BLA transmission. The PL delta-opioid receptor may thus be an effective therapeutic target for anxiety disorders.


Assuntos
Ansiolíticos , Complexo Nuclear Basolateral da Amígdala , Morfinanos , Camundongos , Animais , Masculino , Complexo Nuclear Basolateral da Amígdala/metabolismo , Receptores Opioides delta/agonistas , Receptores Opioides delta/metabolismo , Camundongos Endogâmicos C57BL , Ansiedade , Analgésicos Opioides
6.
Molecules ; 28(22)2023 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-38005269

RESUMO

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED50 (and 95% confidence interval) of 0.70 (0.52-0.97) mg/kg i.p. mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p.) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED50 value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics.


Assuntos
Analgésicos Opioides , Peptídeos Cíclicos , Camundongos , Animais , Analgésicos Opioides/farmacologia , Peptídeos Cíclicos/farmacologia , Receptores Opioides delta/agonistas , Morfina/farmacologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Receptores Opioides mu/agonistas , Peptídeos
7.
Neurosci Lett ; 814: 137468, 2023 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-37660978

RESUMO

Opioid use disorder (OUD) is a chronic and relapsing brain disease that results in significant mortality worldwide. Genetic factors are estimated to contribute to 40%-60% of the liability, with polymorphisms of opioid receptor genes implicated in this disorder. However, the mechanisms underlying these associations are not yet fully understood. In the present study, we first examined the methylation levels in the promoter region of the OPRM1, OPRD1, and OPRK1 genes in 111 healthy controls (HCs) and 120 patients with OUD, and genotyped three tag SNPs in these genes. Correlations between these SNPs and the methylation levels of the CpG sites and expression levels of the genes were analyzed. After identifying the mQTLs and eQTLs, we determined the associations between the mQTLs/eQTLs and susceptibility to and characteristics of OUD in 930 HCs and 801 patients with OUD. Our results demonstrated that SNPs rs1799971 in the OPRM1 gene and rs4654327 in the OPRD1 gene were both mQTLs and eQTLs. We observed unique correlations between mQTLs and methylation levels of several CpG sites in the OUD group compared to the HC group. Interestingly, both the two mQTLs and eQTLs were associated with the susceptibility to OUD. In conclusion, we suppose that mQTLs and eQTLs in genes may underlie the associations between certain risk genetic polymorphisms and OUD. These mQTLs and eQTLs could potentially serve as promising biomarkers for better management of opioid misuse.


Assuntos
Transtornos Relacionados ao Uso de Opioides , Locos de Características Quantitativas , Humanos , Metilação , Genótipo , Transtornos Relacionados ao Uso de Opioides/genética , Polimorfismo de Nucleotídeo Único , Receptores Opioides mu/genética , Receptores Opioides delta/genética
8.
Drug Alcohol Depend ; 250: 110903, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37531661

RESUMO

BACKGROUND: Variants in the delta opioid receptor gene, OPRD1, were associated with opioid use disorder and response to treatment. The study goal was to assess whether OPRD1 variants predict survival and retention in methadone maintenance treatment (MMT). METHODS: Retention and survival time since admission (June 1993 - June 2022) until leaving treatment (for retention), or at the end of follow-up (Dec 2022) (for retention and survival) were analyzed in 488 patients. Vital data was taken from a national registry. Predictors were estimated using Kaplan-Meier and Cox regression models. RESULTS: Longer retention and survival were found for carriers of the T allele of SNP rs204076. This SNP is associated with OPRD1 expression in cortex (GTEx). Carriers of the T allele (n = 251) survived longer compared to non-carriers (24.7 vs. 20.2 years, p = 0.005) and had longer retention (11.2 vs. 8.8 years, p = 0.04). Multivariate analysis identified the T allele as an independent predictor of longer survival time (p = 0.003) and retention (p = 0.009). Additional predictors for survival were no benzodiazepine use after one year in MMT, no hepatitis C, <20 years of opioid usage, and admission at age < 30. Additional predictors for longer retention were no use of other drugs except opioids on admission, and no drugs at one year, as well as methadone dose ≥ 100mg/d at one year and axis I & II DSM-5 psychiatric diagnosis. CONCLUSIONS: The OPRD1 SNP rs204076 and non-genetic predictors contribute to survival time and retention in MMT patients.


Assuntos
Transtornos Relacionados ao Uso de Opioides , Receptores Opioides delta , Humanos , Receptores Opioides delta/genética , Receptores Opioides delta/uso terapêutico , Metadona/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/psicologia , Analgésicos Opioides/uso terapêutico , Benzodiazepinas/uso terapêutico , Tratamento de Substituição de Opiáceos
9.
J Reprod Dev ; 69(4): 192-197, 2023 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-37331801

RESUMO

Gonadal function is often suppressed during lactation in mammals including rodents, ruminants, and primates. This suppression is thought to be mostly due to the inhibition of the tonic (pulsatile) release of gonadotropin-releasing hormone (GnRH) and consequent gonadotropin. Accumulating evidence suggests that kisspeptin neurons in the arcuate nucleus (ARC) play a critical role in the regulation of pulsatile GnRH/gonadotropin release, and kisspeptin mRNA (Kiss1) and/or kisspeptin expression in the ARC are strongly suppressed by the suckling stimuli in lactating rats. This study aimed to examine whether the central enkephalin-δ-opioid receptor (DOR) signaling mediates the suckling-induced suppression of luteinizing hormone (LH) release in lactating rats. Central administration of a selective DOR antagonist increased the mean plasma LH levels and baseline of LH pulses in ovariectomized lactating mother rats compared to vehicle-injected control dams on day 8 of lactation without affecting the number of Kiss1-expressing cells and the intensity of Kiss1 mRNA signals in the ARC. Furthermore, the suckling stimuli significantly increased the number of enkephalin mRNA (Penk)-expressing cells and the intensity of Penk mRNA signals in the ARC compared to non-lactating control rats. Collectively, these results suggest that central DOR signaling, at least in part, mediates the suppression of LH release induced by suckling stimuli in lactating rats via indirect and/or direct inhibition of ARC kisspeptin neurons.


Assuntos
Kisspeptinas , Receptores Opioides delta , Feminino , Ratos , Animais , Kisspeptinas/genética , Lactação , Hormônio Luteinizante , Hormônio Liberador de Gonadotropina , Mamíferos
10.
Int J Mol Sci ; 24(12)2023 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-37373107

RESUMO

Rubiscolins are naturally occurring opioid peptides derived from the enzymatic digestion of the ribulose bisphosphate carboxylase/oxygenase protein in spinach leaves. They are classified into two subtypes based on amino acid sequence, namely rubiscolin-5 and rubiscolin-6. In vitro studies have determined rubiscolins as G protein-biased delta-opioid receptor agonists, and in vivo studies have demonstrated that they exert several beneficial effects via the central nervous system. The most unique and attractive advantage of rubiscolin-6 over other oligopeptides is its oral availability. Therefore, it can be considered a promising candidate for the development of a novel and safe drug. In this review, we show the therapeutic potential of rubiscolin-6, mainly focusing on its effects when orally administered based on available evidence. Additionally, we present a hypothesis for the pharmacokinetics of rubiscolin-6, focusing on its absorption in the intestinal tract and ability to cross the blood-brain barrier.


Assuntos
Receptores Opioides delta , Ribulose-Bifosfato Carboxilase , Ribulose-Bifosfato Carboxilase/metabolismo , Receptores Opioides delta/metabolismo , Oligopeptídeos , Peptídeos Opioides
11.
Int J Neuropsychopharmacol ; 26(7): 513-521, 2023 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-37343217

RESUMO

BACKGROUND: Evidence has accumulated demonstrating the existence of opioid receptor heteromers, and recent data suggest that targeting these heteromers could reduce opioid side effects while retaining therapeutic effects. Indeed, CYM51010 characterized as a MOR (mu opioid receptor)/DOR (delta opioid receptor) heteromer-preferring agonist promoted antinociception comparable with morphine but with less tolerance. In the perspective of developing these new classes of pharmacological agents, data on their putative side effects are mandatory. METHODS: Therefore, in this study, we investigated the effects of CYM51010 in different models related to drug addiction in mice, including behavioral sensitization, conditioned place preference and withdrawal. RESULTS: We found that, like morphine, CYM51010 promoted acute locomotor activity as well as psychomotor sensitization and rewarding effect. However, it induced less physical dependence than morphine. We also investigated the ability of CYM51010 to modulate some morphine-induced behavior. Whereas CYM51010 was unable to block morphine-induced physical dependence, it blocked reinstatement of an extinguished morphine induced-conditioned place preference. CONCLUSIONS: Altogether, our results reveal that targeting MOR-DOR heteromers could represent a promising strategy to block morphine reward.


Assuntos
Morfina , Receptores Opioides delta , Camundongos , Animais , Morfina/farmacologia , Receptores Opioides delta/agonistas , Receptores Opioides mu , Analgésicos Opioides/farmacologia , Recompensa
12.
Environ Toxicol Pharmacol ; 100: 104143, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37146669

RESUMO

This study aimed to determine the effects of nine OPRM1, OPRD1 and OPRK1 polymorphisms on plasma BUP and norbuprenorphine (norBUP) concentrations and various treatment responses in a sample of 122 patients receiving BUP/naloxone. Plasma concentrations of BUP and norBUP were detected by LC-MS/MS. PCR-RFLP method was used to genotype polymorphisms. OPRD1 rs569356 GG had significantly lower plasma norBUP concentration (p = 0.018), dose- (p = 0.049) and dose/kg-normalized norBUP values (p = 0.036) compared with AA. Craving and withdrawal symptoms were significantly higher in OPRD1 rs569356 AG+GG relative to AA. There was a statistically significant difference between the OPRD1 rs678849 genotypes in the intensity of anxiety (13.5 for CT+TT and 7.5 for TT). OPRM1 rs648893 TT (18.8 ± 10.8) was significantly different to CC+CT (14.82 ± 11.3; p = 0.049) in view of the intensity of depression. This current study provides the first data on a prominent effect of the OPRD1 rs569356 variation on BUP pharmacology due to its metabolite norBUP.


Assuntos
Buprenorfina , Transtornos Relacionados ao Uso de Opioides , Humanos , Cromatografia Líquida , Espectrometria de Massas em Tandem , Buprenorfina/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Receptores Opioides delta/genética , Receptores Opioides delta/uso terapêutico
13.
Pain ; 164(10): 2253-2264, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37171192

RESUMO

ABSTRACT: Exposure to severely stressful events during childhood is associated with poor health outcomes in later life, including chronic pain and substance use disorder. However, the mediators and mechanisms are unclear. We investigated the impact of a well-characterized mouse model of early-life adversity, fragmented maternal care (FC) between postnatal day 2 and 9, on nociception, inflammatory hypersensitivity, and responses to morphine. Male and female mice exposed to FC exhibited prolonged basal thermal withdrawal latencies and decreased mechanical sensitivity. In addition, morphine had reduced potency in mice exposed to FC and their development of tolerance to morphine was accelerated. Quantitative PCR analysis in several brain regions and the spinal cords of juvenile and adult mice revealed an impact of FC on the expression of genes encoding opioid peptide precursors and their receptors. These changes included enhanced abundance of δ opioid receptor transcript in the spinal cord. Acute inflammatory hypersensitivity (induced by hind paw administration of complete Freund's adjuvant) was unaffected by exposure to FC. However, after an initial recovery of mechanical hypersensitivity, there was a reappearance in mice exposed to FC by day 15, which was not seen in control mice. Changes in nociception, morphine responses, and hypersensitivity associated with FC were apparent in males and females but were absent from mice lacking δ receptors or ß-arrestin2. These findings suggest that exposure to early-life adversity in mice enhances δ receptor expression leading to decreased basal sensitivity to noxious stimuli coupled with accelerated morphine tolerance and enhanced vulnerability to persistent inflammatory hypersensitivity.


Assuntos
Morfina , Animais , Feminino , Masculino , Camundongos , Analgésicos Opioides/efeitos adversos , Hiperalgesia/etiologia , Hiperalgesia/induzido quimicamente , Morfina/efeitos adversos , Dor/induzido quimicamente , Receptores Opioides delta/genética , Estresse Psicológico , Regulação para Cima
14.
Headache ; 63(5): 621-633, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37183526

RESUMO

OBJECTIVE: The aim of this study was to evaluate whether elevating levels of enkephalin by inhibiting their degradation can attenuate stress-induced migraine-like behaviors in mice. BACKGROUND: Previous studies in animals have suggested the delta opioid receptor (DOR) as a novel migraine target. The primary endogenous ligands for DOR are enkephalins and their levels can be increased by pharmacological inhibition of enkephalinases; however, it is not clear whether enkephalinase inhibition can be efficacious in preclinical migraine models through activation of DOR or whether other opioid receptors might be involved. Further, it is not clear whether opioid receptors in the central nervous system are necessary for these effects. METHODS: This study used a model of repetitive restraint stress in mice that induces periorbital hypersensitivity and priming to the nitric oxide donor sodium nitroprusside (SNP; 0.1 mg/kg). Von Frey filaments were used to measure periorbital mechanical thresholds and grimace scores were evaluated by observing mouse facial features. Animals were treated with the dual enkephalinase inhibitor (DENKI) PL37. RESULTS: On day two post-stress, PL37 given to mice via either intravenous injection (10 mg/kg) or oral gavage (20 mg/kg) significantly attenuated stress-induced periorbital hypersensitivity and facial grimace responses. Additionally, both intravenous (10 mg/kg) and oral gavage (20 mg/kg) of PL37 prior to SNP (0.1 mg/kg) administration on day 14 post-stress significantly reduced SNP-induced facial hypersensitivity. Injection of the DOR antagonist naltrindole (0.1 mg/kg) but not the mu-opioid receptor antagonist CTAP (1 mg/kg) prior to PL37 treatment blocked the effects. Finally, pretreatment of mice with the peripherally restricted opioid receptor antagonist naloxone methiodide (5 mg/kg) blocked the effects of PL37. CONCLUSIONS: These data demonstrate that inhibiting enkephalinases, and thus protecting enkephalins from degradation, attenuates stress-induced migraine-like behavior via activation of peripheral DOR. Peripheral targeting of endogenous opioid signaling may be an effective therapeutic strategy for migraine.


Assuntos
Transtornos de Enxaqueca , Antagonistas de Entorpecentes , Camundongos , Animais , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides delta , Neprilisina , Encefalinas/metabolismo , Encefalinas/farmacologia , Receptores Opioides , Transtornos de Enxaqueca/tratamento farmacológico
15.
Neuropharmacology ; 232: 109526, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37004753

RESUMO

The δ opioid receptor (δOR) is a therapeutic target for the treatment of various neurological disorders, such as migraines, chronic pain, alcohol use, and mood disorders. Relative to µ opioid receptor agonists, δOR agonists show lower abuse liability and may be potentially safer analgesic alternatives. However, currently no δOR agonists are approved for clinical use. A small number of δOR agonists reached Phase II trials, but ultimately failed to progress due to lack of efficacy. One side effect of δOR agonism that remains poorly understood is the ability of δOR agonists to produce seizures. The lack of a clear mechanism of action is partly driven by the fact that δOR agonists range in their propensity to induce seizure behavior, with multiple δOR agonists reportedly not causing seizures. There is a significant gap in our current understanding of why certain δOR agonists are more likely to induce seizures, and what signal-transduction pathway and/or brain area is engaged to produce these seizures. In this review we provide a comprehensive overview of the current state of knowledge of δOR agonist-mediated seizures. The review was structured to highlight which agonists produce seizures, which brain regions have been implicated and which signaling mediators have been examined in this behavior. Our hope is that this review will spur future studies that are carefully designed and aimed to solve the question why certain δOR agonists are seizurogenic. Obtaining such insight may expedite the development of novel δOR clinical candidates without the risk of inducing seizures. This article is part of the Special Issue on "Opioid-induced changes in addiction and pain circuits".


Assuntos
Dor Crônica , Receptores Opioides delta , Humanos , Receptores Opioides delta/agonistas , Ligantes , Encéfalo/metabolismo , Convulsões/induzido quimicamente , Receptores Opioides mu/agonistas , Analgésicos Opioides/efeitos adversos
16.
J Ethnopharmacol ; 309: 116355, 2023 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-36914035

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pain and inflammation are the major symptoms of almost every human disease. Herbal preparations from Morinda lucida are used to treat pain and inflammation in traditional medicine. However, the analgesic and anti-inflammatory activities of some of the plant's chemical constituents are not known. AIM OF THE STUDY: The aim of this study is to evaluate the analgesic and anti-inflammatory activities and possible mechanisms of these activities of iridoids from Morinda lucida. MATERIAL AND METHODS: The compounds were isolated using column chromatography and characterized by NMR spectroscopy and LC-MS. Anti-inflammatory activity was evaluated using carrageenan-induced paw edema. Whereas, the analgesic activity was assessed in the hot plate and acetic acid-induced writhing assays. Mechanistic studies were conducted using pharmacological blockers, determination of antioxidant enzymes, lipid peroxidation, and docking studies. RESULTS: The iridoid, ML2-2 exhibited inverse dose-dependent anti-inflammatory activity (42.62% maximum at 2 mg/kg p. o). ML2-3 produced dose-dependent anti-inflammatory activity (64.52% maximum at 10 mg/kg p. o.). Anti-inflammatory activity of diclofenac sodium was 58.60% at 10 mg/kg p. o. Furthermore, ML2-2 and ML2-3 produced analgesic activity (P < 0.01) of 44.44 ± 5.84 and 54.18 ± 19.01%. at 10 mg/kg p. o. respectively in the hot plate assay and 64.88 and 67.44% in the writhing assay. ML2-2 significantly elevated catalase activity. However, ML2-3 elevated SOD and catalase activity significantly. In the docking studies, both iridoids formed stable crystal complexes with delta and kappa opioid receptors, and the COX-2 enzyme with very low free binding energies (ΔG) from -11.2 to -14.0 kcal/mol. However, they did not bind with the mu opioid receptor. The lower bound RMSD of most of the poses were found to be ≤ 2. Several amino acids were involved in the interactions through various inter molecular forces. CONCLUSION: These results indicate that ML2-2 and ML2-3 possessed very significant analgesic and anti-inflammatory activities via acting as both delta and kappa opioid receptor agonist, elevation of anti-oxidant activity and inhibition of COX-2.


Assuntos
Morinda , Rubiaceae , Humanos , Ciclo-Oxigenase 2/metabolismo , Receptores Opioides delta , Catalase , Iridoides/farmacologia , Iridoides/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Dor/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Carragenina , Inflamação/tratamento farmacológico , Antioxidantes , Superóxido Dismutase/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo
17.
Neuropharmacology ; 232: 109511, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37001727

RESUMO

Delta opioid receptors (DOPs) play an important role in depression and other mood disorders. However, little is known about the underlying physiological mechanisms. The hypothalamic-pituitary-adrenal axis, adult hippocampal neurogenesis, and neuroinflammation are regarded as key pathophysiological factors in depression. In this study, we investigated the influence of DOP activation on those factors in a valid animal model of depression, chronic vicarious social defeat stress (cVSDS) mice. cVSDS mice (male C57BL/6J mice) were produced following a 10-day exposure to witness of social defeat stress, and each evaluation was performed more than 28 days after the stress period. Repeated administrations to cVSDS mice with a selective DOP agonist, KNT-127, both during (10 days) and after (28 days) the stress period respectively improved their decreased social interaction behaviors and increased serum corticosterone levels. When administered during the stress period, KNT-127 suppressed decreases in the hippocampal newborn neuron survival rate in cVSDS mice. Moreover, in both administration paradigms, KNT-127 reduced the number of Iba-1- and CD11b-positive cells in the subgranular zone and the granule cell layer of the hippocampal dentate gyrus, indicating a suppression of cVSDS-induced microglial overactivation. These results suggest that KNT-127 acts over the hypothalamic-pituitary-adrenal axis and regulates neurogenesis and neuroinflammation resulting in anti-stress effects, and the antidepressant-like effects of the DOP agonist are implicated in the suppression of the neuroinflammation. This study presents a new finding on the effects of repeated DOP activations on the pathophysiological states of depression.


Assuntos
Receptores Opioides delta , Derrota Social , Masculino , Camundongos , Animais , Receptores Opioides delta/agonistas , Sistema Hipotálamo-Hipofisário/metabolismo , Doenças Neuroinflamatórias , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal/metabolismo , Analgésicos Opioides/farmacologia , Hipocampo , Giro Denteado/metabolismo , Estresse Psicológico/tratamento farmacológico , Neurogênese , Depressão/tratamento farmacológico
18.
J Physiol ; 601(8): 1483-1500, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36859810

RESUMO

Morphine diminishes pain, but its long-term use is compromised by tolerance and hyperalgesia. Studies implicate δ receptors, ß-arrestin2 and Src kinase in tolerance. We examined whether these proteins are also involved in morphine-induced hypersensitivity (MIH). A common pathway for tolerance and hypersensitivity may provide a single target to guide improved analgesic approaches. We examined mechanical sensitivity using automated von Frey in wild-type (WT) and transgenic male and female C57Bl/6 mice before and after hind paw inflammation by complete Freund's adjuvant (CFA). CFA-evoked hypersensitivity ceased on day 7 in WT but persisted for the 15-day testing period in µ-/- . Recovery was delayed until day 13 in δ-/- . We explored the expression of opioid genes in the spinal cord using quantitative RT-PCR. Restoration to basal sensitivity in WT occurred with increased δ expression. By contrast, κ expression was reduced, while µ remained unchanged. Daily morphine reduced hypersensitivity in WT on day 3 compared to controls; however, hypersensitivity recurred on day 9 and beyond. By contrast, WT had no recurrence of hypersensitivity in the absence of daily morphine. We used ß-arrestin2-/- , δ-/- and Src inhibition by dasatinib in WT to establish whether these approaches, which diminish tolerance, also attenuate MIH. While none of these approaches affected CFA-evoked inflammation or acute hypersensitivity, all caused sustained morphine anti-hypersensitivity, abolishing MIH. Like morphine tolerance, MIH in this model requires δ receptors, ß-arrestin2 and Src activity. Our findings suggest that MIH is caused by a tolerance-induced reduction in endogenous opioid signalling. KEY POINTS: Morphine is effective for treating severe acute pain, but tolerance and hypersensitivity often develop during its use in treating chronic pain. It is unclear whether these detrimental effects share similar mechanisms; if so, it might be possible to develop a single approach to minimise both phenomena. Mice deficient in µ receptors, δ receptors or ß-arrestin2 and wild type mice treated with the Src inhibitor dasatinib exhibit negligible morphine tolerance. We show that these same approaches also prevent the development of morphine-induced hypersensitivity during persistent inflammation. This knowledge identifies strategies, such as the use of Src inhibitors, which may mitigate tolerance and morphine induced hyperalgesia.


Assuntos
Hiperalgesia , Morfina , Camundongos , Masculino , Feminino , Animais , Morfina/efeitos adversos , Hiperalgesia/induzido quimicamente , Analgésicos Opioides/efeitos adversos , Receptores Opioides delta/metabolismo , beta-Arrestina 1/metabolismo , Dasatinibe , Dor , Proteína Tirosina Quinase CSK/metabolismo , Receptores Opioides mu/metabolismo , Camundongos Endogâmicos C57BL , Inflamação
19.
J Med Chem ; 66(6): 3746-3784, 2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-36856340

RESUMO

The global "opioid crisis" has placed enormous pressure on the opioid ligand discovery community to produce novel opioid analgesics with superior opioid-related adverse-effect profiles compared with morphine. In this Perspective, the multitargeted opioid ligand strategy for the discovery of opioid analgesics with superior preclinical therapeutic indices relative to morphine is reviewed and discussed. Dual-targeted µ-opioid (MOP)/δ-opioid (DOP) ligands in which the in vitro DOP antagonist potency at least equals that of the MOP agonist activity, and are devoid of DOP or κ-opioid (KOP) agonist activity, are sufficiently promising candidates to warrant further investigation. Dual-targeted MOP/NOP partial agonists have superior preclinical therapeutic indices to morphine and/or fentanyl in nonhuman primates and are also considered promising. Based on the poor preclinical and clinical therapeutic indices of cebranopadol, which is a full agonist at MOP, DOP, and NOP receptors and a partial agonist at the KOP receptor, this pharmacologic template should be avoided.


Assuntos
Analgesia , Analgésicos Opioides , Animais , Analgésicos Opioides/efeitos adversos , Receptores Opioides mu , Receptores Opioides delta , Ligantes , Dor/tratamento farmacológico , Morfina
20.
Chem Biol Drug Des ; 101(6): 1382-1392, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36813756

RESUMO

6,7-Benzomorphans have been investigated in medicinal chemistry for developing new drugs. This nucleus could be considered a versatile scaffold. The physicochemical properties of benzomorphan N-substituent are crucial in achieving a definite pharmacological profile at opioid receptors. Thus, the dual-target MOR/DOR ligands LP1 and LP2 were obtained through N-substituent modifications. Specifically, LP2, bearing as N-substituent the (2R/S)-2-methoxy-2- phenylethyl group, is a dual-target MOR/DOR agonist and is successful in animal models of inflammatory and neuropathic pain. To obtain new opioid ligands, we focused on the design and synthesis of LP2 analogs. First, the 2-methoxyl group of LP2 was replaced by an ester or acid functional group. Then, spacers of different lengths were introduced at N-substituent. In-vitro, their affinity profile versus opioid receptors has been performed through competition binding assays. Molecular modeling studies were conducted to deeply analyze the binding mode and the interactions between the new ligands and all opioid receptors.


Assuntos
Receptores Opioides delta , Receptores Opioides mu , Animais , Receptores Opioides mu/metabolismo , Receptores Opioides delta/metabolismo , Benzomorfanos/metabolismo , Benzomorfanos/farmacologia , Ligantes , Receptores Opioides , Relação Estrutura-Atividade
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