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1.
Medicine (Baltimore) ; 99(22): e20429, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481444

RESUMO

Determining the clinically optimal dose in methadone maintenance therapy (MMT) is a time-consuming procedure, which considers clinical signs and symptoms.To perform a quantitative trait locus association for identifying genetic variants for MMT dosage that underlie heroin addiction and methadone metabolism and then integrate several genotypic and phenotypic factors are potential predictors for clinically optimal MMT dose for personalized prescription.In total, 316 heroin-dependent patients undergoing MMT were recruited at the Addiction Center of the China Medical University Hospital. A multinomial logistic regression model was used to assess associations between genetic polymorphisms and MMT dosing. The data were randomly separated into training and testing sets. In order to enhance the prediction accuracy and the reliability of the prediction model, we used areas under the receiver operating characteristic curves to evaluate optimal MMT dose in both training and testing sets.Four single nucleotide polymorphisms, namely rs806368 in CNR1, s1386493 in TPH2, s16974799 in CYP2B6, and rs2229205 in OPRL1, were significantly associated with the maximum MMT dose (P < .05). The genetic risk score (GRS) was associated with maximum MMT dose, and after adjustments for age, sex, and body mass index, the GRS remained independently associated with the maximum MMT dose. The area under the receiver operating characteristic curve of the combined GRS and craving score was 0.77 for maximum MMT dose, with 75% sensitivity and 60% specificity.Integrating the GRS and craving scores may be useful in the evaluation of individual MMT dose requirements at treatment initiation. Optimal dose prediction allows clinicians to tailor MMT to each patient's needs.


Assuntos
Fissura , Dependência de Heroína/tratamento farmacológico , Dependência de Heroína/genética , Metadona/administração & dosagem , Entorpecentes/administração & dosagem , Medicina de Precisão , Adulto , Citocromo P-450 CYP2B6/genética , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Humanos , Masculino , Tratamento de Substituição de Opiáceos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptor CB1 de Canabinoide/genética , Receptores Opioides/genética , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Triptofano Hidroxilase/genética
2.
PLoS One ; 15(3): e0229646, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32126112

RESUMO

Kratom is a botanical substance that is marketed and promoted in the US for pharmaceutical opioid indications despite having no US Food and Drug Administration approved uses. Kratom contains over forty alkaloids including two partial agonists at the mu opioid receptor, mitragynine and 7-hydroxymitragynine, that have been subjected to the FDA's scientific and medical evaluation. However, pharmacological and toxicological data for the remaining alkaloids are limited. Therefore, we applied the Public Health Assessment via Structural Evaluation (PHASE) protocol to generate in silico binding profiles for 25 kratom alkaloids to facilitate the risk evaluation of kratom. PHASE demonstrates that kratom alkaloids share structural features with controlled opioids, indicates that several alkaloids bind to the opioid, adrenergic, and serotonin receptors, and suggests that mitragynine and 7-hydroxymitragynine are the strongest binders at the mu opioid receptor. Subsequently, the in silico binding profiles of a subset of the alkaloids were experimentally verified at the opioid, adrenergic, and serotonin receptors using radioligand binding assays. The verified binding profiles demonstrate the ability of PHASE to identify potential safety signals and provide a tool for prioritizing experimental evaluation of high-risk compounds.


Assuntos
Mitragyna/química , Plantas Medicinais/química , Alcaloides de Triptamina e Secologanina/química , Animais , Sítios de Ligação , Células HEK293 , Humanos , Técnicas In Vitro , Simulação de Acoplamento Molecular , Ensaio Radioligante , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos/metabolismo , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/metabolismo , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Alcaloides de Triptamina e Secologanina/farmacocinética , Alcaloides de Triptamina e Secologanina/farmacologia , Relação Estrutura-Atividade
3.
PLoS One ; 15(3): e0229761, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155179

RESUMO

Cyclo-Gly-Pro (CGP) attenuates nociception, however its effects on salivary glands remain unclear. In this study, we investigated the acute effects of CGP on salivary flow and composition, and on the submandibular gland composition, compared with morphine. Besides, we characterized the effects of naloxone (a non-selective opioid receptor antagonist) on CGP- and morphine-induced salivary and glandular alterations in mice. After that, in silico analyses were performed to predict the interaction between CGP and opioid receptors. Morphine and CGP significantly reduced salivary flow and total protein concentration of saliva and naloxone restored them to the physiological levels. Morphine and CGP also reduced several infrared vibrational modes (Amide I, 1687-1594cm-1; Amide II, 1594-1494cm-1; CH2/CH3, 1488-1433cm-1; C = O, 1432-1365cm-1; PO2 asymmetric, 1290-1185cm-1; PO2 symmetric, 1135-999cm-1) and naloxone reverted these alterations. The in silico docking analysis demonstrated the interaction of polar contacts between the CGP and opioid receptor Cys219 residue. Altogether, we showed that salivary hypofunction and glandular changes elicited by CGP may occur through opioid receptor suggesting that the blockage of opioid receptors in superior cervical and submandibular ganglions may be a possible strategy to restore salivary secretion while maintaining antinociceptive action due its effects on the central nervous system.


Assuntos
Gânglios Parassimpáticos/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Peptídeos Cíclicos/farmacologia , Glândulas Salivares/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Sítios de Ligação , Gânglios Parassimpáticos/metabolismo , Gânglios Parassimpáticos/fisiologia , Masculino , Camundongos , Morfina/farmacologia , Nociceptividade , Ligação Proteica , Receptores Opioides/química , Receptores Opioides/metabolismo , Saliva/metabolismo , Glândulas Salivares/metabolismo , Glândulas Salivares/fisiologia
4.
Proc Natl Acad Sci U S A ; 117(5): 2656-2662, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31941713

RESUMO

Slow response to the standard treatment for depression increases suffering and risk of suicide. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, can rapidly alleviate depressive symptoms and reduce suicidality, possibly by decreasing hyperactivity in the lateral habenula (LHb) brain nucleus. Here we find that in a rat model of human depression, opioid antagonists abolish the ability of ketamine to reduce the depression-like behavioral and LHb hyperactive cellular phenotypes. However, activation of opiate receptors alone is not sufficient to produce ketamine-like effects, nor does ketamine mimic the hedonic effects of an opiate, indicating that the opioid system does not mediate the actions of ketamine but rather is permissive. Thus, ketamine does not act as an opiate but its effects require both NMDA and opiate receptor signaling, suggesting that interactions between these two neurotransmitter systems are necessary to achieve an antidepressant effect.


Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Ketamina/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Animais , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Opioides/genética , Receptores Opioides/metabolismo
5.
Curr Med Chem ; 27(9): 1562-1575, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31057099

RESUMO

Morphine and related drugs that act through activating opioid receptors are the most effective analgesics for the relief of severe pain. They have been used for decades, despite the range of unwanted side effects that they produce, as no alternative has been found so far. The major goal of opioid research is to understand the mechanism of action of opioid receptor agonists and to improve the therapeutic utility of opioid drugs. In the search for safer and more potent analgesics, analogs with mixed opioid receptor profile gained a lot of interest. However, recently the concept of biased agonism, that highlights the fact that some ligands are able to differentially activate receptor downstream pathways, became a new approach in the design of novel drug candidates for clinical application. In this review, we summarize current knowledge on the development of opioid ligands of peptide and nonpeptide structure, showing how much opioid pharmacology evolved in recent years.


Assuntos
Manejo da Dor , Analgésicos , Analgésicos Opioides , Humanos , Dor , Receptores Opioides
6.
Support Care Cancer ; 28(3): 1083-1088, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31183560

RESUMO

BACKGROUND: Opioid-induced nausea and vomiting (OINV) is induced by opioid receptor stimulation of chemoreceptor trigger zones and vestibular apparatus by opioids. Naldemedine tosylate (NALD) is a peripherally acting non-selective opioid receptor antagonist, used for opioid-induced constipation (OIC). However, the effect of NALD on OINV had not yet been investigated. In this retrospective study, we investigated the secondary effects of NALD on OINV. METHOD: Patients who received sustained-release oral morphine or oxycodone preparation were enrolled in the study. Patients who used NALD (0.2 mg) within 2 days of opioid initiation were included in the analysis. The use of rescue antiemetics within 7 days from opioid initiation was defined as OINV expression. Patients who received antiemetics before opioid initiation or those who received chemotherapy around 4 days from opioid initiation were excluded from the analysis. The incidence of OINV was compared between patients who used and did not use NALD. RESULTS: In total, 982 patients were included in the study. Among them, 89 patients who received NALD and 614 patients who did not receive NALD were analyzed. The incidence of OINV in patients who used NALD was significantly lower than that of patients who did not use NALD (36.0% vs. 47.2%, p = 0.046). CONCLUSION: For patients with constipation, using NALD at an early stage of opioid initiation might have secondary benefits, such as relief from OINV, besides improvement of OIC. To confirm the effectiveness of NALD for OINV, the symptom grade and intensity during concomitant use of NALD should be observed in a future study.


Assuntos
Analgésicos Opioides/efeitos adversos , Antieméticos/uso terapêutico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/uso terapêutico , Náusea/prevenção & controle , Vômito/prevenção & controle , Idoso , Analgésicos Opioides/uso terapêutico , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/prevenção & controle , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Morfina/efeitos adversos , Morfina/uso terapêutico , Naltrexona/uso terapêutico , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Oxicodona/efeitos adversos , Oxicodona/uso terapêutico , Receptores Opioides/efeitos dos fármacos , Estudos Retrospectivos , Vômito/induzido quimicamente , Vômito/tratamento farmacológico
7.
N Engl J Med ; 382(3): 222-232, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31702883

RESUMO

BACKGROUND: Difelikefalin is a peripherally restricted and selective agonist of kappa opioid receptors that are considered to be important in modulating pruritus in conditions such as chronic kidney disease. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients undergoing hemodialysis who had moderate-to-severe pruritus to receive either intravenous difelikefalin (at a dose of 0.5 µg per kilogram of body weight) or placebo three times per week for 12 weeks. The primary outcome was the percentage of patients with an improvement (decrease) of at least 3 points from baseline at week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS; scores range from 0 to 10, with higher scores indicating greater itch intensity). The secondary outcomes included the change from baseline in itch-related quality-of-life measures, the percentage of patients with an improvement of at least 4 points in the WI-NRS score at week 12, and safety. RESULTS: A total of 378 patients underwent randomization. A total of 82 of 158 patients (51.9%) in the difelikefalin group had a decrease of at least 3 points in the WI-NRS score (primary outcome), as compared with 51 of 165 (30.9%) in the placebo group. The imputed percentage of patients with a decrease of at least 3 points in the WI-NRS score was 49.1% in the difelikefalin group, as compared with 27.9% in the placebo group (P<0.001). Difelikefalin also resulted in a significant improvement from baseline to week 12 in itch-related quality of life as measured by the 5-D itch scale and the Skindex-10 scale. The imputed percentage of patients with a decrease of at least 4 points in the WI-NRS score at week 12 was significantly greater in the difelikefalin group than in the placebo group (37.1% [observed data: 64 of 158 patients] vs. 17.9% [observed data: 35 of 165 patients], P<0.001). Diarrhea, dizziness, and vomiting were more common in the difelikefalin group than in the placebo group. CONCLUSIONS: Patients treated with difelikefalin had a significant reduction in itch intensity and improved itch-related quality of life as compared with those who received placebo. (Funded by Cara Therapeutics; KALM-1 ClinicalTrials.gov number, NCT03422653.).


Assuntos
Falência Renal Crônica/complicações , Piperidinas/uso terapêutico , Prurido/tratamento farmacológico , Receptores Opioides/agonistas , Diálise Renal , Uremia/complicações , Adulto , Método Duplo-Cego , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Prurido/etiologia , Qualidade de Vida , Resultado do Tratamento
8.
J Agric Food Chem ; 68(7): 1877-1883, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31402656

RESUMO

The antihypertensive activity of two αs1-casein-derived peptides and casein hydrolysate containing these sequences was evaluated in the presence of naloxone. The activity was abolished by this opioid antagonist at 2, 4, and 6 h post-administration. Similarly, the antihypertensive effect of the αs1-casein peptides 90RYLGY94 (-23.8 ± 2.5 mmHg) and 143AYFYPEL149 (-21.1 ± 3.2 mmHg) at 5 mg/kg of body weight was antagonized by the co-administration of naloxone. Because peptide 143AYFYPEL149 had recently shown opioid activity, a molecular dynamic simulation of this peptide with human µ-opioid receptor was performed to demonstrate its favorable structure and interaction energy, despite the presence of Ala at the N terminus. Altogether, these results revealed that the in vivo effect on systolic blood pressure of the studied αs1-casein peptides is mediated by interaction with opioid receptors and the antihypertensive activity of casein hydrolysate can be very likely ascribed to them with the possible contribution of other mechanisms.


Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Caseínas/administração & dosagem , Hipertensão/tratamento farmacológico , Peptídeos/administração & dosagem , Receptores Opioides/metabolismo , Animais , Anti-Hipertensivos/química , Caseínas/química , Bovinos , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Simulação de Dinâmica Molecular , Naloxona/administração & dosagem , Peptídeos/química , Ratos , Ratos Endogâmicos SHR , Receptores Opioides/química , Receptores Opioides/genética
10.
J Ethnopharmacol ; 248: 112276, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31593812

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia divinorum Epling & Játiva is a Mexican plant used not only in rituals but also in traditional medicine for pain relief. One of the most known bioactive compounds is salvinorin A, which acts centrally in kappa-type opioid receptors. AIM OF THE STUDY: Despite its traditional use as a medicinal plant, there is not enough scientific investigation to reinforce its potential as analgesic. In this study, Salvia divinorum antinociceptive activity was evaluated in experimental models of nociceptive pain; the writhing test and formalin-induced licking behavior in mice. MATERIAL AND METHODS: Different Salvia divinorum extracts were prepared by maceration at room temperature in increased polarity (hexane, ethyl acetate and methanol). The ethyl acetate extract (EAEx) was chosen in order to be fractioned and to obtain a mixture of salvinorins. The antinociceptive effect of EAEx (3, 10, 30, and 100 mg/kg, i.p.) was compared with that of tramadol (a partial opioid agonist analgesic drug, 30 mg/kg, i.p.) and the mixture of salvinorins (30 mg/kg, i.p.). In addition, a participation of opioids (naloxone, NX 1 and/or 3 mg/kg, i.p.) and serotonin 5-HT1A receptors (WAY100635, 0.32 mg/kg, i.p.) was investigated as possible inhibitory neurotransmission involved. RESULTS: As a result, the EAEx produced significant and dose-dependent antinociceptive effect concerning salvinorins constituents. This effect was blocked in the presence of NX and WAY100635 in the abdominal test, but only by NX in the formalin-induced licking behavior. Whereas, the effect of salvinorins mixture involved opioids and serotonin 5-HT1A receptors. CONCLUSION: Data provide evidence of the potential of this species, where salvinorin A is in part responsible bioactive constituent involving participation of the opioids and/or 5-HT1A serotonin receptors depending on the kind of pain model explored.


Assuntos
Analgésicos/uso terapêutico , Diterpenos Clerodânicos/uso terapêutico , Dor/tratamento farmacológico , Salvia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Folhas de Planta , Receptor 5-HT1A de Serotonina/fisiologia , Receptores Opioides/fisiologia
11.
Molecules ; 24(24)2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31817441

RESUMO

Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously activate two or more targets may produce a more desirable drug profile than selectively targeted compounds has created an opportunity for a new approach to developing more effective medications. Here, in order to better understand the role of the neurokinin system in opioid-induced antinociception, we report the synthesis, structure-activity relationship, and pharmacological characterization of a series of hybrids combining opioid pharmacophores with either substance P (SP) fragments or neurokinin receptor (NK1) antagonist fragments. On the bases of the in vitro biological activities of the hybrids, two analogs, opioid agonist/NK1 antagonist Tyr-[d-Lys-Phe-Phe-Asp]-Asn-d-Trp-Phe-d-Trp-Leu-Nle-NH2 (2) and opioid agonist/NK1 agonist Tyr-[d-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH2 (4), were selected for in vivo tests. In the writhing test, both hybrids showed significant an antinociceptive effect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant differences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids.


Assuntos
Analgésicos , Antagonistas de Entorpecentes , Antagonistas do Receptor de Neuroquinina-1 , Nociceptividade/efeitos dos fármacos , Oligopeptídeos , Receptores da Neurocinina-1 , Receptores Opioides , Analgésicos/farmacologia , Animais , Linhagem Celular , Tolerância a Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas de Entorpecentes/química , Antagonistas de Entorpecentes/farmacologia , Antagonistas do Receptor de Neuroquinina-1/química , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Receptores da Neurocinina-1/agonistas , Receptores da Neurocinina-1/metabolismo , Receptores Opioides/agonistas , Receptores Opioides/metabolismo
12.
Yakugaku Zasshi ; 139(11): 1403-1415, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685737

RESUMO

For my Ph.D. research topic, I isolated endogenous morphine-like analgesic dipeptide, kyotorphin, which mediates Met-enkephalin release, and discovered kyotorphin synthetase, a putative receptor and antagonist. Furthermore, I succeeded in purifying µ-opioid receptor and functional reconstitution with purified G proteins. After receiving my full professor position at Nagasaki University in 1996, I worked on two topics of research, molecular mechanisms of chronic pain through lysophosphatidic acid (LPA) and identification and characterization of neuroprotective protein, prothymosin α. In a series of studies, we have shown that LPA signaling defines the molecular mechanisms of neuropathic pain and fibromyalgia in terms of development and maintenance. Above all, the discovery of feed-forward system in LPA production and pain memory may contribute to better understanding of chronic pain and future analgesic drug discovery. Regarding prothymosin α, we first discovered it as neuronal necrosis-inhibitory molecule through two independent mechanisms, such as toll-like receptor and F0/F1 ATPase, both which protect neurons through indirect mechanisms. Prothymosin α is released by non-classical and non-vesicular mechanisms on various stresses, such as ischemia, starvation, and heat-shock. Thus it may be called a new type of neuroprotective damage-associated molecular patterns (DAMPs)/Alarmins. Heterozygotic mice showed a defect in memory-learning and neurogenesis as well as anxiogenic behaviors. Small peptide, P6Q derived from prothymosin α retains neuroprotective actions, which include blockade of cerebral hemorrhage caused by late treatment with tissue plasminogen activator in the stroke model in mice.


Assuntos
Dor Crônica/etiologia , Dor Crônica/genética , Fármacos Neuroprotetores , Precursores de Proteínas , Receptores de Ácidos Lisofosfatídicos/fisiologia , Transdução de Sinais/fisiologia , Timosina/análogos & derivados , Animais , Endorfinas , Humanos , Camundongos , Precursores de Proteínas/metabolismo , ATPases Translocadoras de Prótons , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores Opioides , Acidente Vascular Cerebral , Timosina/metabolismo , Receptores Toll-Like
13.
PLoS One ; 14(11): e0224657, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31703066

RESUMO

We investigated a potential use of a 3D tetraculture brain microphysiological system (BMPS) for neurotoxic chemical agent screening. This platform consists of neuronal tissue with extracellular matrix (ECM)-embedded neuroblastoma cells, microglia, and astrocytes, and vascular tissue with dynamic flow and membrane-free culture of the endothelial layer. We tested the broader applicability of this model, focusing on organophosphates (OPs) Malathion (MT), Parathion (PT), and Chlorpyrifos (CPF), and chemicals that interact with GABA and/or opioid receptor systems, including Muscimol (MUS), Dextromethorphan (DXM), and Ethanol (EtOH). We validated the BMPS platform by measuring the neurotoxic effects on barrier integrity, acetylcholinesterase (AChE) inhibition, viability, and residual OP concentration. The results show that OPs penetrated the model blood brain barrier (BBB) and inhibited AChE activity. DXM, MUS, and EtOH also penetrated the BBB and induced moderate toxicity. The results correlate well with available in vivo data. In addition, simulation results from an in silico physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model that we generated show good agreement with in vivo and in vitro data. In conclusion, this paper demonstrates the potential utility of a membrane-free tetraculture BMPS that can recapitulate brain complexity as a cost-effective alternative to animal models.


Assuntos
Encéfalo/fisiologia , Imageamento Tridimensional , Neurotoxinas/toxicidade , Organofosfatos/toxicidade , Testes de Toxicidade , Acetilcolinesterase/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Microfluídica , Neurotoxinas/farmacocinética , Organofosfatos/farmacocinética , Receptores de GABA/metabolismo , Receptores Opioides/metabolismo , Fatores de Tempo
14.
Molecules ; 24(22)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752279

RESUMO

The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as µ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although N-[methyl-11C]morphine, -codeine and -heroin did not show significant binding in vivo. [11C]Diprenorphine ([11C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the µ-preferring agonist [11C]carfentanil ([11C]Caf). These two tracers have the property of being displaceable by endogenous opioid peptides in living brain, thus potentially serving in a competition-binding model. Indeed, many clinical PET studies with [11C]DPN or [11C]Caf affirm the release of endogenous opioids in response to painful stimuli. Numerous other PET studies implicate µ-OR signaling in aspects of human personality and vulnerability to drug dependence, but there have been very few clinical PET studies of µORs in neurological disorders. Tracers based on naltrindole, a non-peptide antagonist of the δ-preferring endogenous opioid enkephalin, have been used in PET studies of δORs, and [11C]GR103545 is validated for studies of κORs. Structures such as [11C]NOP-1A show selective binding at ORL-1 receptors in living brain. However, there is scant documentation of δ-, κ-, or ORL1 receptors in healthy human brain or in neurological and psychiatric disorders; here, clinical PET research must catch up with recent progress in radiopharmaceutical chemistry.


Assuntos
Imagem Molecular , Receptores Opioides/metabolismo , Animais , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encefalopatias/diagnóstico por imagem , Encefalopatias/etiologia , Encefalopatias/metabolismo , Humanos , Ligantes , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Imagem Molecular/métodos , Neuroimagem/métodos , Peptídeos/química , Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons , Traçadores Radioativos , Receptores Opioides/agonistas , Receptores Opioides/química
15.
Molecules ; 24(23)2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31779072

RESUMO

The opioid receptors modulate a variety of biological functions, including pain, mood, and reward. As a result, opioid ligands are being explored as potential therapeutics for a variety of indications. Multifunctional opioid ligands, which act simultaneously at more than one type of opioid receptor, show promise for use in the treatment of addiction, pain, and other conditions. Previously, we reported the creation of bifunctional kappa opioid receptor (KOR) agonist/mu opioid receptor (MOR) partial agonist ligands from the classically delta opioid receptor (DOR) antagonist selective dimethyltyrosine-tetrahydroisoquinoline (Dmt-Tiq) scaffold through the addition of a 7-benzyl pendant on the tetrahydroisoquinoline ring. This study further explores the structure-activity relationships surrounding 7-position pendants on the Dmt-Tiq scaffold. Some analogues maintain a KOR agonist/MOR partial agonist profile, which is being explored in the development of a treatment for cocaine addiction. Others display a MOR agonist/DOR antagonist profile, which has potential to be used in the creation of a less addictive pain medication. Ultimately, we report the synthesis and in vitro evaluation of novel opioid ligands with a variety of multifunctional profiles.


Assuntos
Analgésicos Opioides/metabolismo , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Células CHO , Linhagem Celular , Cricetulus , Humanos , Dor/tratamento farmacológico , Dor/metabolismo , Manejo da Dor/métodos , Receptores Opioides/metabolismo , Relação Estrutura-Atividade
16.
Elife ; 82019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31589142

RESUMO

Identifying neurons that have functional opioid receptors is fundamental for the understanding of the cellular, synaptic and systems actions of opioids. Current techniques are limited to post hoc analyses of fixed tissues. Here we developed a fluorescent probe, naltrexamine-acylimidazole (NAI), to label opioid receptors based on a chemical approach termed 'traceless affinity labeling'. In this approach, a high affinity antagonist naltrexamine is used as the guide molecule for a transferring reaction of acylimidazole at the receptor. This reaction generates a fluorescent dye covalently linked to the receptor while naltrexamine is liberated and leaves the binding site. The labeling induced by this reagent allowed visualization of opioid-sensitive neurons in rat and mouse brains without loss of function of the fluorescently labeled receptors. The ability to locate endogenous receptors in living tissues will aid considerably in establishing the distribution and physiological role of opioid receptors in the CNS of wild type animals.


Assuntos
Química Encefálica , Neurônios/química , Receptores Opioides/análise , Coloração e Rotulagem/métodos , Animais , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Fluorometria/métodos , Camundongos Endogâmicos C57BL , Ratos Sprague-Dawley
17.
Eur J Med Chem ; 182: 111634, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472474

RESUMO

In order to discover a novel type of analgesic, we investigated dual activity ligands with TRPV1 antagonism and mu-opioid receptor affinity with the goal of eliciting synergistic analgesia while avoiding the side effects associated with single targeting. Based on a combination approach, a series of 4-benzyl-4-(dimethylamino)piperidinyl analogues were designed, synthesized and evaluated for their receptor activities. Among them, compound 49 exhibited the most promising dual-acting activity toward TRPV1 and the mu-opioid receptor in vitro. In vivo,49 displayed potent, dose-dependent antinociceptive activity in both the 1st and 2nd phases in the formalin assay. Consistent with its postulated mechanism, we confirmed that in vivo, as in vitro, compound 49 both antagonized TRPV1 and functioned as a mu-opioid agonist. This result indicates that dual-acting TRPV1 antagonist/mu-opioid ligands can be made and represent a new and promising class of analgesic.


Assuntos
Analgésicos Opioides/farmacologia , Descoberta de Drogas , Dor/tratamento farmacológico , Receptores Opioides/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Células CHO , Células Cultivadas , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Dor/metabolismo , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo
18.
Int J Neuropsychopharmacol ; 22(11): 710-723, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31562746

RESUMO

BACKGROUND: Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. METHODS: We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. RESULTS: Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. CONCLUSION: Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Estimulantes do Sistema Nervoso Central/administração & dosagem , Expressão Gênica , Metanfetamina/administração & dosagem , Núcleo Accumbens/metabolismo , Receptores de Orexina/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Feminino , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Long-Evans , Receptores Opioides/metabolismo , Caracteres Sexuais , Vasopressinas/metabolismo
19.
Int J Mol Sci ; 20(17)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484312

RESUMO

Opioid use disorder is classified as a chronic recurrent disease of the central nervous system (CNS) which leads to personality disorders, co-morbidities and premature death. It develops as a result of long-term administration of various abused substances, along with morphine. The pharmacological action of morphine is associated with its stimulation of opioid receptors. Opioid receptors are a group of G protein-coupled receptors and activation of these receptors by ligands induces significant molecular changes inside the cell, such as an inhibition of adenylate cyclase activity, activation of potassium channels and reductions of calcium conductance. Recent data indicate that other signalling pathways also may be involved in morphine activity. Among these are phospholipase C, mitogen-activated kinases (MAP kinases) or ß-arrestin. The present review focuses on major mechanisms which currently are considered as essential in morphine activity and dependence and may be important for further studies.


Assuntos
Adenilil Ciclases/metabolismo , Dependência de Morfina/metabolismo , Adenilil Ciclases/genética , Animais , Humanos , Dependência de Morfina/genética , Receptores Opioides/genética , Receptores Opioides/metabolismo , beta-Arrestinas/metabolismo
20.
Chem Biol Interact ; 311: 108790, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31400342

RESUMO

Preclinical assays play a key role in research in research on the neurobiology of pain and the development of novel analgesics. Drugs available for the treatment of inflammatory pain are not fully effective and show adverse effects. Thus, we investigated the antinociceptive, anti-inflammatory and anti-hyperalgesic effects of bis(3-amino-2-pyridine) diselenide (BAPD), a new analgesic drug prototype. BAPD effects were investigated using nociception models induced by chemical (glutamate), immunologic (Freund's Complete Adjuvant - CFA) and thermal stimuli in Swiss mice. Mice were orally (p.o.) treated with BAPD (0.1-50 mg/kg) 30 min prior to the glutamate and hot-plate tests and a time-course (0.5 up to 8 h) of the antinociceptive effect of BAPD (50 mg/kg, p. o.) was evaluated in a CFA model. In the CFA model, BAPD effects on cyclooxygenase-2 (COX-2), tumor necrosis factor (TNFα) and interferon-γ (INF-γ) expression, myeloperoxidase (MPO) activity, oxidative (2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels) and histological parameters were evaluated. The safety of the compound (50 and 300 mg/kg, p. o.) was verified for 72 h. BAPD reduced the licking time induced by glutamate and caused an increase in latency response to thermal stimulus. Naloxone reversed the antinociceptive effect of BAPD. Paw edema formation induced by glutamate or CFA injection was reduced by BAPD. Mechanical hyperalgesia induced by CFA was attenuated by BAPD. BAPD did not protect against the increase in MPO activity and decrease of the 2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels induced by CFA. BAPD protected against histological alterations and reduction on the levels of gene expression COX-2 and INF-γ in the paw of mice exposed to CFA. BAPD was safe at the doses and time evaluated. BAPD exerts acute antinociceptive, anti-inflammatory and anti-hyperalgesic actions, suggesting that it may represent an alternative in the future development of new therapeutic strategies.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Interferon gama/metabolismo , Nociceptividade/efeitos dos fármacos , Receptores Opioides/metabolismo , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/genética , Edema/tratamento farmacológico , Edema/patologia , Comportamento Exploratório/efeitos dos fármacos , Pé/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Interferon gama/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/patologia , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Opioides/genética , Testes de Toxicidade Aguda , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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