Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.186
Filtrar
1.
Molecules ; 26(20)2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34684749

RESUMO

The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia.


Assuntos
Dor Crônica/tratamento farmacológico , Receptores de Angiotensina/efeitos dos fármacos , Receptores Opioides mu/efeitos dos fármacos , Analgésicos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Humanos , Neuralgia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Manejo da Dor/métodos , Receptores de Angiotensina/metabolismo , Receptores Opioides/agonistas , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo
2.
Anesthesiology ; 135(3): 482-493, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34237134

RESUMO

BACKGROUND: Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and µ receptors produces analgesia with reduced side effects in nonhuman primates. METHODS: The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with µ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses. RESULTS: Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] µg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] µg/kg). Pretreatment with antagonists selective for nociceptin and µ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose-response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 µg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 µg; 3,009 ± 1,474 scratches). CONCLUSIONS: In nonhuman primates, the µ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/µ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol.


Assuntos
Indóis/administração & dosagem , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Receptores Opioides/agonistas , Compostos de Espiro/administração & dosagem , Analgésicos Opioides/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Fentanila/administração & dosagem , Injeções Espinhais , Macaca mulatta , Masculino , Peptídeos Opioides/administração & dosagem , Receptores Opioides/fisiologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/fisiologia
3.
Mol Pharmacol ; 100(1): 7-18, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33958480

RESUMO

Agonists at the nociceptin opioid peptide receptor (NOP) are under investigation as therapeutics for nonaddicting analgesia, opioid use disorder, Parkinson's disease, and other indications. NOP full and partial agonists have both been of interest, particularly since NOP partial agonists show a reduced propensity for behavioral disruption than NOP full agonists. Here, we investigated the in vitro pharmacological properties of chemically diverse NOP receptor agonists in assays measuring functional activation of the NOP receptor such as guanosine 5'-O-[gamma-thio]triphosphate (GTPγS) binding, cAMP inhibition, G protein-coupled inwardly rectifying potassium (GIRK) channel activation, phosphorylation, ß-arrestin recruitment and receptor internalization. When normalized to the efficacy of the natural agonist nociceptin/orphanin FQ (N/OFQ), we found that different functional assays that measure intrinsic activity produce inconsistent levels of agonist efficacy, particularly for ligands that were partial agonists. Agonist efficacy obtained in the GTPγS assay tended to be lower than that in the cAMP and GIRK assays. These structurally diverse NOP agonists also showed differential receptor phosphorylation profiles at the phosphosites we examined and induced varying levels of receptor internalization. Interestingly, although the rank order for ß-arrestin recruitment by these NOP agonists was consistent with their ability to induce receptor internalization, their phosphorylation signatures at the time point we investigated were not indicative of the levels of ß-arrestin recruitment or internalization induced by these agonists. It is possible that other phosphorylation sites, yet to be identified, drive the recruitment of NOP receptor ensembles and subsequent receptor trafficking by some nonpeptide NOP agonists. These findings potentially help understand NOP agonist pharmacology in the context of ligand-activated receptor trafficking. SIGNIFICANCE STATEMENT: Chemically diverse agonist ligands at the nociceptin opioid receptor G protein-coupled receptor showed differential efficacy for activating downstream events after receptor binding, in a suite of functional assays measuring guanosine 5'-O-[gamma-thio]triphosphate binding, cAMP inhibition, G protein-coupled inwardly rectifying protein channel activation, ß-arrestin recruitment, receptor internalization and receptor phosphorylation. These analyses provide a context for understanding nociceptin opioid peptide receptor (NOP) agonist pharmacology driven by ligand-induced differential NOP receptor signaling.


Assuntos
Proteínas de Ligação ao GTP/metabolismo , Receptores Opioides/agonistas , Bibliotecas de Moléculas Pequenas/farmacologia , beta-Arrestinas/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Estrutura Molecular , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química
4.
Curr Pain Headache Rep ; 25(7): 46, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33970352

RESUMO

PURPOSE OF REVIEW: Although opioids are excellent analgesics, they are associated with severe short- and long-term side effects that are especially concerning for the treatment of chronic pain. Peripherally acting opioid receptor agonists promise to mitigate the more serious centrally mediated side effects of opioids, and the goal of this paper is to identify and elaborate on recent advances in these peripheral opioid receptor therapeutics. RECENT FINDINGS: Peripheral opioid receptor agonists are effective analgesics that at the same time circumvent the problem of centrally mediated opioid side effects by (1) preferentially targeting peripheral opioid receptors that are often the source of the pain and (2) their markedly diminished permeability or activity across the blood-brain barrier. Recent novel bottom-up approaches have been notable for the design of therapeutics that are either active only at inflamed tissue, as in the case of fentanyl-derived pH-sensitive opioid ligands, or too bulky or hydrophilic to cross the blood-brain barrier, as in the case of morphine covalently bound to hyperbranched polyglycerols. Recent innovations in peripheral opioid receptor therapeutics of pH-sensitive opioid ligands and limiting opioid permeability across the blood-brain barrier have had promising results in animal models. While this is grounds for optimism that some of these therapeutics will be efficacious in human subjects at a future date, each drug must undergo individualized testing for specific chronic pain syndromes to establish not only the nuances of each drug's therapeutic effect but also a comprehensive safety profile.


Assuntos
Receptores Opioides/agonistas , Receptores Opioides/uso terapêutico , Analgésicos/efeitos adversos , Analgésicos/uso terapêutico , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Humanos
5.
J Med Chem ; 64(10): 6523-6548, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33956427

RESUMO

Because of the problems associated with opioids, drug discovery efforts have been employed to develop opioids with reduced side effects using approaches such as biased opioid agonism, multifunctional opioids, and allosteric modulation of opioid receptors. Receptor targets such as adrenergic, cannabinoid, P2X3 and P2X7, NMDA, serotonin, and sigma, as well as ion channels like the voltage-gated sodium channels Nav1.7 and Nav1.8 have been targeted to develop novel analgesics. Several enzymes, such as soluble epoxide hydrolase, sepiapterin reductase, and MAGL/FAAH, have also been targeted to develop novel analgesics. In this review, old and recent targets involved in pain signaling and compounds acting at these targets are summarized. In addition, strategies employed to reduce side effects, increase potency, and efficacy of opioids are also elaborated. This review should aid in propelling drug discovery efforts to discover novel analgesics.


Assuntos
Analgésicos/química , Descoberta de Drogas , Receptores Opioides/química , Agonistas Adrenérgicos/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Humanos , Dor/tratamento farmacológico , Receptores Opioides/agonistas , Receptores Opioides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Sódio Disparados por Voltagem/química , Canais de Sódio Disparados por Voltagem/metabolismo
6.
J Med Chem ; 64(10): 6656-6669, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33998786

RESUMO

The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr1 and Thr5 at the N-terminal portion of N/OFQ(1-13)-NH2 with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silico studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an in vivo model of cough.


Assuntos
Peptídeos/química , Receptores Opioides mu/agonistas , Receptores Opioides/agonistas , Animais , Sítios de Ligação , Tosse/induzido quimicamente , Tosse/tratamento farmacológico , Modelos Animais de Doenças , Cobaias , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Simulação de Dinâmica Molecular , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Receptores Opioides/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Relação Estrutura-Atividade
7.
Transl Res ; 234: 1-19, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33727192

RESUMO

It is essential that safe and effective treatment options be available to patients suffering from chronic pain. The emergence of an opioid epidemic has shaped public opinions and created stigmas surrounding the use of opioids for the management of pain. This reality, coupled with high risk of adverse effects from chronic opioid use, has led chronic pain patients and their healthcare providers to utilize nonopioid treatment approaches. In this review, we will explore a number of cellular reorganizations that are associated with the development and progression of chronic pain. We will also discuss the safety and efficacy of opioid and nonopioid treatment options for chronic pain. Finally, we will review the evidence for adenylyl cyclase type 1 (AC1) as a novel target for the treatment of chronic pain.


Assuntos
Dor Crônica/tratamento farmacológico , Inibidores de Adenilil Ciclases/uso terapêutico , Adenilil Ciclases/fisiologia , Analgésicos não Narcóticos/uso terapêutico , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/classificação , Analgésicos Opioides/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticonvulsivantes/uso terapêutico , Antidepressivos/uso terapêutico , Dor Crônica/etiologia , Dor Crônica/fisiopatologia , Descoberta de Drogas , Humanos , Epidemia de Opioides , Transtornos Relacionados ao Uso de Opioides , Receptores Opioides/agonistas , Pesquisa Médica Translacional
8.
J Ethnopharmacol ; 270: 113872, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33485984

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Mu opioid receptor (MOR) is mainly a drug target for analgesia. Opioid-like agonists such as morphine have been clinically used for analgesia but have potential adverse effects. MOR antagonists have been demonstrated to alleviate these side effects. Plants (Carthamus tinctorius L, Cynanchum otophyllum C. K. Schneid., Coffea arabica L., Prinsepia utilis Royle and Lepidium meyenii Walp.) and Ganoderma fungi (Ganoderma hainanense J. D. Zhao, Ganoderma capense (Lloyd) Teng, Ganoderma cochlear (Blume et Nees) Bres., Ganoderma resinaceum Boud and Ganoderma applanatum (Pers.) Pat.) are traditional medicines with beneficial effects on immunoregulation, analgesia and the nervous system, but whether MORs are engaged in their effects remains unknown. AIM OF THE STUDY: This work aimed to identify MOR ligands among compounds isolated from the above-mentioned 10 species, and to investigate selectivity against four opioid receptor subtypes. By analyzing the structure-activity relationship and off-target effects, we could provide a new direction for the future development of MOR drugs. MATERIALS AND METHODS: Four opioid receptor subtype models, including MOR, delta (DOR), kappa (KOR) and nop (NOR), were established with a label-free phenotypic dynamic mass redistribution assay to systematically profile the pharmacological properties of known ligands. Then, 82 natural compounds derived from the 10 species were screened against MOR to identify new ligands. The selectivity of the new ligands was characterized against the four subtypes, and off-target effects were also investigated on eight G protein-coupled receptors (GPCRs). RESULTS: The pharmacological properties of known ligands on transfected HEK293T-MOR, HEK293-DOR, HEK293-KOR and HEK293-NOR cell lines were characterized. Seven compounds purified from Ganoderma cochlear (Blume et Nees) Bres. and Carthamus tinctorius L were MOR antagonists with micromolar potency. Among them, compound 35 showed the strongest antagonistic activity on MOR with an IC50 value of 10.0 ± 3.0 µM. To a certain extent, these seven new antagonists, exhibited antagonistic activity on the other opioid receptor subtypes, and they had almost no effect on other GPCRs, including CB1, CB2, M2 and beta2AR. Additionally, a compound from Lepidium meyenii Walp. displayed MOR agonistic activity. CONCLUSIONS: The established screening models opened new avenues for the discovery and evaluation of opioid receptor ligand selectivity. Together, the novel MOR antagonists and agonists will enrich the inventory of MOR ligands and benefit related therapies.


Assuntos
Produtos Biológicos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides/metabolismo , Produtos Biológicos/química , Técnicas Biossensoriais/métodos , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Células HEK293 , Humanos , Ligantes , Receptores Opioides/agonistas , Receptores Opioides/genética , Relação Estrutura-Atividade
9.
Br J Anaesth ; 126(2): 367-376, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33220939

RESUMO

BACKGROUND: Opioid-induced immunomodulation may be of particular importance in triple-negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and oncological outcomes and explored patterns of opioid receptor expression in TNBC. METHODS: Consecutive patients with stage I-III primary TNBC were identified from a prospectively maintained database. Opioid receptor expression patterns in the tumour microenvironment were analysed using publicly available bulk and single-cell RNA-seq data. RESULTS: A total of 1143 TNBC cases were retrospectively analysed. In multivariable analysis, higher intraoperative opioid dose was associated with favourable recurrence-free survival, hazard ratio 0.93 (95% confidence interval 0.88-0.99) per 10 oral morphine milligram equivalents increase (P=0.028), but was not significantly associated with overall survival, hazard ratio 0.96 (95% confidence interval 0.89-1.02) per 10 morphine milligram equivalents increase (P=0.2). Bulk RNA-seq analysis of opioid receptors showed that OPRM1 was nearly non-expressed. Compared with normal breast tissue OGFR, OPRK1, and OPRD1 were upregulated, while TLR4 was downregulated. At a single-cell level, OPRM1 and OPRD1 were not detectable; OPRK1 was expressed mainly on tumour cells, whereas OGFR and TLR4 were more highly expressed on immune cells. CONCLUSIONS: We found a protective effect of intraoperative opioids on recurrence-free survival in TNBC. Opioid receptor expression was consistent with a net protective effect of opioid agonism, with protumour receptors either not expressed or downregulated, and antitumour receptors upregulated. In this era of personalised medicine, efforts to differentiate the effects of opioids across breast cancer subtypes (and ultimately individual patients) should continue.


Assuntos
Analgésicos Opioides/administração & dosagem , Cuidados Intraoperatórios , Mastectomia , Recidiva Local de Neoplasia/prevenção & controle , Receptores Opioides/agonistas , Neoplasias de Mama Triplo Negativas/cirurgia , Analgésicos Opioides/efeitos adversos , Bases de Dados Factuais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Cuidados Intraoperatórios/efeitos adversos , Cuidados Intraoperatórios/mortalidade , Mastectomia/efeitos adversos , Mastectomia/mortalidade , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Receptores Opioides/genética , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Microambiente Tumoral
10.
Chem Biodivers ; 18(1): e2000871, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33351271

RESUMO

Nociceptin receptor (NOP) belongs to the family of opioid receptors but was discovered and characterized much later than the so called classical opioid receptors, µ, δ and κ (or MOP, DOP and KOP, resp.). Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of this receptor and it controls numerous important functions in the central nervous system and in the periphery, so its analogs may be developed as innovative drugs for the treatment of a variety of conditions and pathological states. Availability of potent and selective ligands with high affinity to NOP receptor is essential to fully understand the role of NOP-N/OFQ system in the body, which in turn may lead to designing novel therapeutics. Here, we have focused on reviewing the structure of potent peptide-based agonists, antagonists, biased analogs and bivalent ligands that target NOP receptor.


Assuntos
Descoberta de Drogas , Peptídeos Opioides/química , Receptores Opioides/metabolismo , Sequência de Aminoácidos , Humanos , Ligantes , Antagonistas de Entorpecentes/química , Antagonistas de Entorpecentes/metabolismo , Peptídeos Opioides/metabolismo , Receptores Opioides/agonistas , Receptores Opioides/química , Relação Estrutura-Atividade
11.
Neurosci Lett ; 745: 135582, 2021 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-33346075

RESUMO

The presence of opioid receptors in the cuneiform nucleus (CnF), which is a mesencephalic area, and their involvement in the central cardiovascular responses have been shown. Therefore, this study is designed to examine the possible role of mu- (µ) and delta- (δ) opioid receptors in the CnF in the cardiovascular responses in normotensive and hemorrhagic hypotensive rats. Following anesthesia and the recording of the blood pressure, the agonist and antagonist of µ- (morphine and naloxone) and δ- (D-Pen 2, 5]-Enkephalin hydrate (DPDPE) and naltridole) receptors were microinjected into the CnF. In the hemorrhagic groups, the drugs were microinjected into the nucleus 2 min after withdrawing 15 % of the total blood volume (TBV). Time-course changes (Δ) in the mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) were obtained and compared with the control and hemorrhage groups. Microinjecting morphine in both normotensive and hemorrhagic rats significantly decreased ΔSBP, ΔMAP, and ΔHR; also, naloxone significantly increased all these parameters. The cardiovascular effects of DPDPE and naltridole were not significant in the normotensive rats; however, DPDPE attenuated only the tachycardia induced by the hypotensive hemorrhage. The findings of this study revealed that the opioid receptors in the CnF had an inhibitory effect on the cardiovascular parameters in both normotensive and hypotensive hemorrhagic conditions and these effects were mostly mediated by µ-opioid receptors.


Assuntos
Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Hemorragia/fisiopatologia , Hipotensão/fisiopatologia , Formação Reticular Mesencefálica/fisiologia , Receptores Opioides/fisiologia , Analgésicos Opioides/administração & dosagem , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hemorragia/induzido quimicamente , Hipotensão/induzido quimicamente , Masculino , Microinjeções/métodos , Formação Reticular Mesencefálica/efeitos dos fármacos , Morfina/administração & dosagem , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Ratos , Ratos Wistar , Receptores Opioides/agonistas
12.
J Med Chem ; 63(19): 10782-10795, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901477

RESUMO

Nociceptin/orphanin FQ (N/OFQ) controls different biological functions via selective stimulation of the N/OFQ peptide (NOP) receptor. The pleiotropic actions of N/OFQ may limit the development of NOP ligands as innovative drugs in different therapeutic areas. The pharmacological concept of functional selectivity (aka biased agonism) might be useful for amplifying beneficial actions and/or counteracting side effects. Thus, molecules with large bias factors toward G protein or ß arrestin are required for investigating the translational value of NOP biased modulation. Herein, the biased behavior of a heterogeneous library of NOP-targeting peptide derivatives was evaluated in vitro with the aim to provide possible insights into the structural determinants that govern the selective activation of G protein versus ß-arrestin. Our results demonstrate that lipidation of N/OFQ(1-13)-NH2 is a useful strategy for obtaining G protein biased agonists for the NOP receptor.


Assuntos
Peptídeos Opioides/farmacologia , Fragmentos de Peptídeos/agonistas , Receptores Opioides/agonistas , Animais , Proteínas de Ligação ao GTP/química , Fragmentos de Peptídeos/química , Receptores Opioides/química , Relação Estrutura-Atividade
13.
Behav Pharmacol ; 31(8): 792-797, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32804774

RESUMO

Mu-opioid receptor (MOR) agonists are highly efficacious for the treatment of pain but have significant abuse liability. Recently, we reported that nalfurafine, when combined with oxycodone at a certain ratio, reduced the reinforcing effects of oxycodone in rats while producing additive antinociceptive effects. Questions remain, however, including if the combination will function as a reinforcer in drug-naïve rats, and if the combination produces aversive effects that could explain nalfurafine's ability to reduce oxycodone self-administration? In the present study, we investigated nalfurafine's ability to reduce acquisition of oxycodone self-administration when the two were self-administered as a mixture in drug-naïve rats and nalfurafine's ability to attenuate a conditioned place preference (CPP) induced by oxycodone. In the self-administration study, male Sprague-Dawley rats self-administered intravenous injections of oxycodone (0.056 mg/kg/injection), an oxycodone/nalfurafine combination (0.056/0.0032 mg/kg/injection), or saline under fixed-ratio schedules of reinforcement for 20 days to compare rates of acquisition of drug taking. In the CPP assay, male Sprague-Dawley rats received subcutaneous injections of either saline, oxycodone (3.2 mg/kg), nalfurafine (0.18 mg/kg), or an oxycodone/nalfurafine combination at the same ratio used in the self-administration study (3.2 mg/kg/0.18 mg/kg). All subjects self-administering oxycodone alone met acquisition criteria. However, only 13% of subjects self-administering oxycodone/nalfurafine met criteria, and no subjects acquired self-administration of saline. Oxycodone, but not nalfurafine alone or the oxycodone/nalfurafine combination, produced rewarding effects in rats in the CPP test. These findings suggest that the combination of oxycodone and nalfurafine will be less habit forming in opioid-naïve patients than oxycodone alone.


Assuntos
Morfinanos/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Receptores Opioides kappa/agonistas , Compostos de Espiro/farmacologia , Analgésicos Opioides/farmacologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Morfinanos/metabolismo , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Oxicodona/efeitos adversos , Oxicodona/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides/agonistas , Receptores Opioides/metabolismo , Receptores Opioides kappa/metabolismo , Reforço Psicológico , Recompensa , Autoadministração , Compostos de Espiro/metabolismo , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle
14.
Drugs ; 80(14): 1443-1453, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32749653

RESUMO

Pain management in both outpatient and inpatient settings demands a multidisciplinary approach entailing medical, physical and psychological therapies. Among these, multimodal analgesic regimens stand out as a promising treatment options. Cyclo-oxygenase (COX) inhibitor/opioid receptor agonist combinations hold great potential as effective pillars in the multimodal pain management by providing adequate analgesia with fewer safety risks due to COX inhibitors' opioid-sparing effect. Thus, these combinations, either freely or in fixed-dose formulation, offer a feasible option for the prescribing clinicians who seek to maximise therapeutic effect while simultaneously minimise adverse effects. The selection of the appropriate non-steroidal anti-inflammatory drug (NSAID) and opioid agent at optimal doses is essential. It should be tailored to the patients' analgesic necessities, and his/her gastrointestinal and cardiovascular risk, and potential concurrent aspirin use. Moreover, it should allow for addiction risk and the potential opioid-induced bowel dysfunction and constipation. To ensure an optimal match between the characteristics of the patient and the properties of the chosen medication, and to guide adequate and well-tolerated treatment decisions, it is of paramount importance to expand clinicians' knowledge of the currently available COX inhibitor/opioid receptor agonist combinations. This invited narrative review deals with the literature evidence covering the components of multimodal opioid-sparing analgesic regimens. Also, it provides insights into the clinically relevant choice criteria to ensure a patient-tailored analgesia.


Assuntos
Analgésicos Opioides/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Dor/tratamento farmacológico , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Humanos , Dor/metabolismo , Manejo da Dor , Receptores Opioides/agonistas
15.
Neuropeptides ; 82: 102059, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32600667

RESUMO

Bipolar disorder is a psychiatric pathology characterized by biphasic mood episodes of mania or hypomania and depression. The pharmacotherapy of bipolar disorder has significant adverse effects impairing treatment adherence and patient quality of life. The N/OFQ-NOP receptor system has been widely implicated with mood disorders. Clinical and preclinical findings suggest antidepressants actions for NOP antagonists. More recently, the administration of NOP agonists has shown to promote depressant states. The present study aimed to investigate the effects of non-peptide NOP ligands in methylphenidate-induced manic-like behavior in mice. The NOP agonist Ro 65-6570 (0.01-1 mg/kg, ip), at the higher dose, did not affect spontaneous locomotion per se, but prevented the methylphenidate (10 mg/kg, sc)-induced hyperlocomotion. The NOP partial agonist AT-090 (0.001-0.03 mg/kg, ip) and the NOP antagonist SB-612111 (1-10 mg/kg, ip) did not significantly affect the psychostimulant-induced hyperactivity. Experiments performed with mice lacking the NOP receptor (NOP(-/-)) demonstrated that the treatment with methylphenidate induced similar hyperlocomotion in NOP(-/-) and NOP(+/+) mice. In conclusion, these findings suggest a potential role for NOP agonists in the prevention of manic states, especially by counteracting the hyperactivity symptom of bipolar patients. However, more studies are necessary in order to evaluate these compounds in other features of bipolar disorder.


Assuntos
Antimaníacos/administração & dosagem , Transtorno Bipolar/fisiopatologia , Hipercinese/fisiopatologia , Imidazóis/administração & dosagem , Metilfenidato/administração & dosagem , Receptores Opioides/fisiologia , Compostos de Espiro/administração & dosagem , Animais , Feminino , Hipercinese/induzido quimicamente , Camundongos , Receptores Opioides/agonistas , Ácido Valproico/administração & dosagem
16.
Int J Mol Sci ; 21(11)2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32485929

RESUMO

Post-burn pruritus is the pruritus that occurs after burn during the rehabilitation and healing process of burn wounds. The post-burn pruritus is a common and serious complication of burn injury, which severely lowers the quality of life of the patient. Many potential treatments are available for pruritus but there is no consensus of the best single treatment yet. The precise mechanism of post-burn pruritus has not been elucidated, but it appears to have pruritogenic and neuropathic aspects. Clinically, post-burn pruritus tends to be intractable to conventional treatment but rather responds to neuroleptic agents, such as gabapentin and pregabalin. During wound healing, various neuropeptides secreted from the nerves of the skin control epidermal and vascular proliferation and connective tissue cells. When keratinocytes are activated by an itch-inducing substance, they secrete a variety of inflammatory substances that increase the susceptibility of the itch receptor. There are two mechanisms underlying post-burn neuropathic pruritus. The first one is peripheral sensitization. The second one is the intact nociceptor hypothesis. An effective treatment for post-burn pruritus will also be effective in other neuropathic and intractable itching. In this review, we summarized the interaction and mechanism of keratinocytes, immune cells, and nerve fibers related to post-burn pruritus.


Assuntos
Antipsicóticos/farmacologia , Queimaduras/complicações , Gabapentina/farmacologia , Pregabalina/farmacologia , Prurido/tratamento farmacológico , Prurido/etiologia , Animais , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Inflamação , Queratinócitos/metabolismo , Antagonistas de Entorpecentes/farmacologia , Neuropeptídeos/metabolismo , Ondansetron/farmacologia , Receptores Opioides/agonistas , Cicatrização
17.
Peptides ; 132: 170348, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32574695

RESUMO

This paper is the forty-first consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2018 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (2), the roles of these opioid peptides and receptors in pain and analgesia in animals (3) and humans (4), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (5), opioid peptide and receptor involvement in tolerance and dependence (6), stress and social status (7), learning and memory (8), eating and drinking (9), drug abuse and alcohol (10), sexual activity and hormones, pregnancy, development and endocrinology (11), mental illness and mood (12), seizures and neurologic disorders (13), electrical-related activity and neurophysiology (14), general activity and locomotion (15), gastrointestinal, renal and hepatic functions (16), cardiovascular responses (17), respiration and thermoregulation (18), and immunological responses (19).


Assuntos
Analgésicos Opioides/farmacologia , Comportamento/efeitos dos fármacos , Aprendizagem/fisiologia , Transtornos Mentais/tratamento farmacológico , Peptídeos Opioides/metabolismo , Dor/tratamento farmacológico , Receptores Opioides/agonistas , Animais , Humanos , Transtornos Mentais/metabolismo , Antagonistas de Entorpecentes/farmacologia , Peptídeos Opioides/agonistas , Peptídeos Opioides/antagonistas & inibidores , Peptídeos Opioides/farmacologia , Dor/metabolismo
18.
J Urol ; 204(6): 1150-1159, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32516030

RESUMO

PURPOSE: We reviewed the literature surrounding the role of opioids and their receptors in urological malignancy. Recent studies have suggested clinically significant effects of agonism or antagonism of opioid receptors on cancer related outcomes and tumorigenesis. The focus of these efforts has centered on nonurological malignancies. However, a compelling body of evidence is growing in the fields of prostate, bladder and kidney cancer. MATERIALS AND METHODS: A systematic review of English language articles published through 2020 was conducted with key phrases related to kidney, bladder or prostate cancer, and opioids or narcotics. A total of 837 unique records were identified, of which 49 were selected for full text review and 33 were included in the qualitative analysis. Eight records were identified via citation review and 1 study was recently presented at a national meeting. RESULTS: Retrospective reviews suggest poorer disease specific and recurrence-free survival with increased perioperative opioid administration in patients undergoing prostate or bladder cancer surgery. However, the data are controversial. Kappa opioid receptors are implicated in both proliferation and inhibition of prostate cancer cell growth across in vitro studies, with a proposed interaction with the androgen cascade. Similarly opioid growth factor receptor is highly expressed in prostate cancer cells and repressed by androgens. Prostate cancer tissue stains more intensely for the mu opioid receptor, and patients with higher expression have poorer oncologic outcomes. Opioid agonism in vitro induces urothelial cell carcinoma proliferation, migration and invasion, with possible additional influence from interactions with the bradykinin b2 receptor. Agonism of the mu, kappa and delta opioid receptors induces renal cell carcinoma tumorigenesis, possibly via upregulation of survivin. Meanwhile, opioid growth factor receptor agonism has the opposite effect in renal cell carcinoma. CONCLUSIONS: Evidence surrounding the role of opioids and their receptors in urological malignancy is provocative and should serve as an impetus for further investigation.


Assuntos
Analgésicos Opioides/efeitos adversos , Dor do Câncer/tratamento farmacológico , Carcinogênese/efeitos dos fármacos , Receptores Opioides/metabolismo , Neoplasias Urológicas/patologia , Analgésicos Opioides/administração & dosagem , Dor do Câncer/etiologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Invasividade Neoplásica/patologia , Manejo da Dor/efeitos adversos , Manejo da Dor/métodos , Período Perioperatório , Próstata/efeitos dos fármacos , Próstata/patologia , Receptores Opioides/agonistas , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Neoplasias Urológicas/complicações , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/terapia
19.
Nihon Yakurigaku Zasshi ; 155(3): 145-148, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32378631

RESUMO

Alcohol dependence is one of the psychiatric disorders affecting over 1 million people in Japan. Mesolimbic dopamine neuron projecting from ventral tegmental area to nucleus accumbens (Reward system) plays important roles in alcohol dependence including other dependence. Accumulating evidence indicates that the endogenous opioid system regulate this reward system. That is, alcohol stimulates the release of endogenous opioid peptides such as ß-endorphin and dynorphin in the brain. ß-endorphin activates µ-opioid receptor leading to euphoric mood and positive reinforcement, while dynorphin activates κ-opioid receptor leading to dysphoric mood and negative reinforcement. These euphoric/dysphoric mood and reinforcement effects via endogenous opioid systems are suggested to be implicated in repeated alcohol intake in patients with alcohol dependence. Nalmefene acts as an antagonist at µ- and δ-opioid receptor and a partial agonist at κ-opioid receptor. Preclinical studies have shown that nalmefene reduced the alcohol intake in alcohol preference rats. In clinical trials, as-needed use of nalmefene with psychosocial support reduced the number of heavy-drinking days and total alcohol consumption. These results suggest that nalmefene modulates the alcohol-induced euphoric/dysphoric mood via opioid system and thereby contribute to reduction in alcohol consumption in patients with alcohol dependence. Here, we summarize the implications of opioid system in alcohol dependence and pharmacological profiles of nalmefene in preclinical and clinical studies.


Assuntos
Alcoolismo/tratamento farmacológico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides/agonistas , Animais , Ensaios Clínicos como Assunto , Humanos , Japão , Naltrexona/farmacologia , Ratos
20.
ChemMedChem ; 15(14): 1322-1329, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32412162

RESUMO

Peptide-based agonists of the µ opioid receptor (µOR) are promising therapeutic candidates for pain relief with reduced side effects compared to morphine. A deep understanding of µOR-ligand interactions is necessary for future design of peptide-based opioid analgesics. To explore the requirements of the µOR binding pocket, eight new analogues of our cyclic peptide Tyr-c[d-Lys-Phe-Phe-Asp]NH2 displaying high µOR affinity were synthesized, in which Phe in either the third or fourth position was replaced by various derivatives of this amino acid (ß3 -Phe, homoPhe, ß3 -homoPhe and PhGly). The aim of this research was to examine the structural effects of such modifications on the bioactivity, and both experimental and theoretical methods were used. The binding of the cyclic analogues to all three OR types (µ, δ, κ) was assessed by radioligand competitive binding assay, and their functional activity was determined in a calcium mobilization assay. In order to provide structural hypotheses explaining the obtained experimental affinities, the complexes of the cyclic peptides with µOR were subjected to molecular modeling.


Assuntos
Peptídeos Cíclicos/farmacologia , Fenilalanina/farmacologia , Receptores Opioides/agonistas , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Fenilalanina/química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...