RESUMO
Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We recently reported a bifunctional peptide-based hybrid LENART01 combining dermorphin and ranatensin pharmacophores, which displays activity to the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) in rat brains and spinal cords. In this study, we investigated the in vitro binding and functional activities to the human MOR and the in vivo pharmacology of LENART01 in mice after subcutaneous administration. In vitro binding assays showed LENART01 to bind and be selective to the human MOR over the other opioid receptor subtypes and delta, kappa and nociceptin receptors. In the [35S]GTPγS binding assay, LENART01 acted as a potent and full agonist to the human MOR. In mice, LENART01 produced dose-dependent antinociceptive effects in formalin-induced inflammatory pain, with increased potency than morphine. Antinociceptive effects were reversed by naloxone, indicating MOR activation in vivo. Behavioral studies also demonstrated LENART01's properties to induce less adverse effects without locomotor dysfunction and withdrawal syndrome compared to conventional opioid analgesics, such as morphine. LENART01 is the first peptide-based MOR-D2R ligand known to date and the first dual MOR-dopamine D2R ligand for which in vivo pharmacology is reported with antinociceptive efficacy and reduced opioid-related side effects. Our current findings may pave the way to new pain therapeutics with limited side effects in acute and chronic use.
Assuntos
Analgésicos Opioides , Oligopeptídeos , Ácido Pirrolidonocarboxílico/análogos & derivados , Receptores Opioides , Humanos , Ratos , Animais , Camundongos , Analgésicos Opioides/farmacologia , Ligantes , Morfina , Peptídeos Opioides/farmacologia , Dor/tratamento farmacológicoRESUMO
Some new hemorphin-4 analogs with structures of Xxx-Pro-Trp-Thr-NH2 and Tyr-Yyy-Trp-Thr-NH2, where Xxx is 2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid or 2-amino-3-(4-dibenzylamino-2,6-dimethylphenyl)propanoic acid, and Yyy is (2S,4S)-4-amino-pyrrolidine-2-carboxylic acid, were synthesized and characterized by electrochemical and spectral analyses. In vivo anticonvulsant and antinociceptive activities of peptide derivatives were studied after intracerebroventricular injection in mice. The therapeutic effects of the modified peptides on seizures and pain in mice were evaluated to provide valuable insights into the potential applications of the novel compounds. Electrochemical characterization showed that the compounds behave as weak protolytes and that they are in a soluble, stable molecular form at physiological pH values. The antioxidant activity of the peptides was evaluated with voltammetric analyses, which were confirmed by applying the 2,2-Diphenyl-1-picrylhydrazyl method. The compounds showed satisfactory results regarding their structural stability, reaching the desired centers for the manifestation of biological activity without hydrolysis processes at 37°C and physiological pH. Dm-H4 and H4-P1 exhibited 100% and 83% potency to suppress the psychomotor seizures in the 6-Hz test compared to 67% activity of H4. Notably, only the H4-P1 had efficacy in blocking the tonic component in the maximal electroshock test with a potency comparable to H4. All investigated peptides containing unnatural conformationally restricted amino acids showed antinociceptive effects. The analogs Db-H4 and H4-P1 showed the most pronounced and long-lasting effect in both experimental models of pain induced by thermal and chemical stimuli. Dm-H4 produced a dose-dependent thermal antinociception and H4-P2 inhibited only formalin-induced pain behavior.
Assuntos
Convulsões , Animais , Camundongos , Masculino , Convulsões/tratamento farmacológico , Relação Estrutura-Atividade , Anticonvulsivantes/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Dor/tratamento farmacológico , Aminoácidos/química , Aminoácidos/farmacologia , Aminoácidos/síntese química , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Analgésicos/farmacologia , Analgésicos/síntese química , Analgésicos/química , Relação Dose-Resposta a Droga , Modelos Animais de Doenças , Peptídeos Opioides/farmacologia , Peptídeos Opioides/síntese química , Peptídeos Opioides/química , Analgésicos Opioides/farmacologia , Analgésicos Opioides/síntese química , Analgésicos Opioides/químicaRESUMO
The Nociceptin/Orphanin FQ (N/OFQ) peptide and its receptor NOP are highly expressed within several regions of the mesolimbic system, including the ventral tegmental area (VTA). Evidence indicates that the N/OFQ-NOP receptor system is involved in reward processing and historically it has been proposed that activation of NOP receptors attenuates the motivation for substances of abuse. However, recent findings demonstrated that drug self-administration and relapse to drug-seeking are also attenuated after administration of NOP receptor antagonists. Here, to shed light on the mechanisms through which NOP receptor blockers modulate these processes, we utilized ex vivo patch-clamp recordings to investigate the effect of the selective NOP receptor antagonist LY2817412 on VTA dopaminergic (DA) function in male rats. Results showed that, similar to the endogenous NOP receptor agonist N/OFQ, LY2817412 reduced the spontaneous basal firing discharge of VTA DA neurons. Consistently, we found that NOP receptors are expressed both in VTA DA and GABA cells and that LY2817412 slice perfusion increased GABA release onto VTA DA cells. Finally, in the attempt to dissect the role of postsynaptic and presynaptic NOP receptors, we tested the effect of N/OFQ and LY2817412 in the presence of GABA receptors blockers. Results showed that the effect of LY2817412 was abolished following pretreatment with GABABR, but not GABAAR, blockers. Conversely, inhibition of DA neuronal activity by N/OFQ was unaffected by blockade of GABA receptors. Altogether, these results suggest that both NOP receptor agonists and antagonists can decrease VTA DA neuronal activity, but through distinct mechanisms of action. The effect of NOP receptor antagonists occurs through a GABABR-mediated mechanism while NOP receptor agonists seem to act via a direct effect on VTA DA neurons.
Assuntos
Dopamina , Receptores Opioides , Ratos , Masculino , Animais , Receptores Opioides/metabolismo , Área Tegmentar Ventral/metabolismo , Receptor de Nociceptina , Receptores de GABA-B , Nociceptina , Neurônios Dopaminérgicos/metabolismo , Ácido gama-Aminobutírico , Peptídeos Opioides/farmacologiaRESUMO
Although the involvement of ß-endorphin (ß-ERP) in vertebrate reproduction has been suggested, its role in testicular activity is not clear in fish. We describe the influence of ß-ERP on spermatogenesis in a cichlid fish in the present paper. In comparison to the control group, the administration of ß-ERP (3 µg) caused a significant increase in the number of spermatogonia-A and spermatids. Following treatment with ß-ERP (6 µg), a significant increase in the number of spermatogonia-A was observed, whereas the numbers of all the other germ cells, excluding spermatogonia-B, significantly decreased in comparison to those in the control group. In addition, treatment of fish with 6 µg ß-ERP resulted in a significant reduction in the dimensions of the lumen and seminiferous lobules, the level of immunopositive androgen receptor (AR) expression in Sertoli cells, and the percentage of luteinizing hormone (LH) immunolabeled in the pituitary compared to those in the control group or the group treated with 3 µg ß-ERP. In contrast, the intensity of AR immunoreactivity and the percentage of LH immunolabeling were substantially increased in fish treated with 3 µg ß-ERP compared to those in the control group. These findings reveal for the first time that a low dose of ß-ERP stimulates the recruitment of spermatogonia as well as spermateleosis, whereas a high concentration affects the recruitment of germ cells prior to meiotic division in tilapia. These results suggest that ß-ERP exerts modulatory effects at the testicular and hypophysial levels through alterations in AR expression and LH secretory activity, respectively, in teleosts.
Assuntos
Testículo , Tilápia , Masculino , Animais , Testículo/metabolismo , Tilápia/metabolismo , beta-Endorfina/metabolismo , beta-Endorfina/farmacologia , Peptídeos Opioides/metabolismo , Peptídeos Opioides/farmacologia , Espermatogênese , Hormônio Luteinizante/metabolismo , EspermatogôniasRESUMO
Cold injury or frostbite is a common medical condition that causes serious clinical complications including sensory abnormalities and chronic pain ultimately affecting overall well-being. Opioids are the first-choice drug for the treatment of frostbite-induced chronic pain; however, their notable side effects, including sedation, motor incoordination, respiratory depression, and drug addiction, present substantial obstacle to their clinical utility. To address this challenge, we have exploited peripheral mu-opioid receptors as potential target for the treatment of frostbite-induced chronic pain. In this study, we investigated the effect of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripheral mu-opioid receptor agonist, on frostbite injury and hypersensitivity induced by deep freeze magnet exposure in rats. Animals with frostbite injury displayed significant hypersensitivity to mechanical, thermal, and cold stimuli which was significant ameliorated on treatment with different doses of DALDA (1, 3, and 10 mg/kg) and ibuprofen (100 mg/kg). Further, molecular biology investigations unveiled heightened oxido-nitrosative stress, coupled with a notable upregulation in the expression of TRP channels (TRPA1, TRPV1, and TRPM8), glial cell activation, and neuroinflammation (TNF-α, IL-1ß) in the sciatic nerve, dorsal root ganglion (DRG), and spinal cord of frostbite-injured rats. Treatment with DALDA leads to substantial reduction in TRP channels, microglial activation, and suppression of the inflammatory cascade in the ipsilateral L4-L5 DRG and spinal cord of rats. Overall, findings from the present study suggest that activation of peripheral mu-opioid receptors mitigates chronic pain in rats by modulating the expression of TRP channels and suppressing glial cell activation and neuroinflammation.
Assuntos
Congelamento das Extremidades , Microglia , Doenças Neuroinflamatórias , Peptídeos Opioides , Ratos Sprague-Dawley , Animais , Masculino , Ratos , Congelamento das Extremidades/tratamento farmacológico , Congelamento das Extremidades/complicações , Congelamento das Extremidades/patologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Hiperalgesia/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Peptídeos Opioides/metabolismo , Peptídeos Opioides/farmacologia , Peptídeos Opioides/uso terapêutico , Dor/tratamento farmacológico , Dor/metabolismo , Dor/patologia , Receptores Opioides mu/metabolismo , Receptores Opioides mu/agonistas , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
The Nociceptin/Orphanin FQ (N/OFQ) system has been shown to modulate various aspects of long-term memory. It is therefore important to study the effects on memory impairment by nociceptin receptor (NOP) agonists under preclinical development. In the present study, we investigated the effect of systemic injection of two small molecule selective NOP agonists, AT-202 and AT-524, in the object location memory task in male and female mice. Since high doses of NOP agonists have been shown to induce sedation, we first determined the sedative doses for the two compounds and found them to be higher in female than in male mice. We then observed that sub-sedative doses of NOP agonists administered before learning, induced memory impairment during a test session performed 24 h later. Again, female mice were less sensitive to the amnesic effects than males. On the contrary, in male mice, NOP agonists did not produce amnesia when they were injected after learning, suggesting that they do not affect the consolidation of object location memory. Finally, repeated administration of high doses of NOP agonists over 7 days did not impair long-term spatial memory. Together, our data show for the first time that NOP receptor agonists impair the acquisition of object location memory with sex-dependent potency but do not affect memory consolidation, and that repeated stimulation of the receptor does not compromise long-term episodic-like spatial memory.
Assuntos
Peptídeos Opioides , Receptores Opioides , Feminino , Camundongos , Masculino , Animais , Peptídeos Opioides/farmacologia , Receptor de Nociceptina , Aprendizagem , Memória de Longo Prazo , Hipnóticos e SedativosRESUMO
This paper is the forty-fifth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2022 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 (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Assuntos
Analgesia , Analgésicos não Narcóticos , Animais , Humanos , Feminino , Gravidez , Peptídeos Opioides/farmacologia , Analgésicos Opioides , Tolerância a MedicamentosRESUMO
The compelling demand of a consummate analgesic medication without addiction is rising due to the clinical mistreatment. Additionally, the series of severe untoward effects usually deterred the utilization while coping with serious pain. As a possible turning point, we revealed that compound 14 is a dual agonist of mu opioid receptor (MOR) and nociceptin-orphanin FQ opioid peptide (NOP) receptor in this study. More importantly, compound 14 achieves pain relieving at very small doses, meanwhile, reduces several unwanted side effects such as constipation, reward, tolerance and withdrawal effects. Here, we evaluated the antinociception and side effects of this novel compound from wild type and humanized mice to further develop a safer prescription analgesic drug.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Receptores Opioides mu , Camundongos , Animais , Receptores Opioides mu/agonistas , Receptores Opioides/agonistas , Receptor de Nociceptina , Peptídeos Opioides/farmacologia , Peptídeos Opioides/uso terapêutico , Analgésicos Opioides/efeitos adversos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Analgésicos/efeitos adversos , NociceptinaRESUMO
The enkephalins are known to regulate many physiological functions, including reproduction in vertebrates. However, the role of leucine-enkephalin (L-ENK) in the ovarian recrudescence activity of reptiles is not known. In the present study, we studied the influence of L-ENK on seasonal and FSH-induced ovarian recrudescence during the breeding and non-breeding phases of the cycle in the tropical and subtropical gecko Hemidactylus frenatus. In the first experiment, treatment with 5 and 25 µg L-ENK resulted in a dose-dependent inhibitory effect on the hypothalamic gonadotropin-releasing hormone (GnRH) neurons and ovary, as indicated by a significantly decreased percent area of GnRH-immunoreactive (GnRH-ir) fibres in the median eminence and pars distalis of the pituitary gland, concomitant with complete absence of stage V (late vitellogenic) follicles in the ovary compared to those of experimental controls. In the second experiment, administration of FSH to lizards in the regression phase stimulated the recruitment of stage IV and V (vitellogenic) follicles in contrast to their absence in initial controls or treatment controls. However, similar treatment of FSH in combination with 25 µg L-ENK did not result in the development of stage IV or V follicles. Together, these results suggest for the first time that treatment with 5 and 25 µg L-ENK exerts a dose-dependent inhibitory effect on the hypothalamic GnRH release into the median eminence and pituitary gland, leading to the blockade of ovarian recrudescence. These results also suggest a possible direct inhibitory effect of L-ENK at the level of the ovary in the gecko.
Assuntos
Lagartos , Ovário , Feminino , Animais , Leucina , Folículo Ovariano , Encefalina Leucina/farmacologia , Peptídeos Opioides/farmacologia , Estações do Ano , Hormônio Liberador de Gonadotropina/farmacologia , Gonadotropinas/farmacologia , Hormônio Foliculoestimulante , Lagartos/fisiologiaRESUMO
The treatment of hard-to-heal chronic wounds is still a major medical problem and an economic and social burden. In this work, we examine the proregenerative potential of two peptides, G11 (a trypsin-resistant analogue of growth hormone-releasing hormone [GHRH]) and biphalin (opioid peptide), and their combination in vitro on human fibroblasts (BJ). G11, biphalin and their combination exhibited no toxicity against BJ cells. On the contrary, these treatments significantly stimulated proliferation and migration of fibroblasts. Under inflammatory conditions (LPS-induced BJ cells), we noticed that the tested peptides decreased the levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and interleukin 1ß (IL-1ß). This was correlated with diminished phosphorylation levels of p38 kinase, but not those of ERK1/2. We found also that G11, biphalin and their combination activated the ERK1/2 signalling pathway, which has been previously implicated in promigratory activity of some regeneration enhancers, including opioids or GHRH analogues. Potential application of their combination requires further work, in particular in vivo experiments, in which the organism-level relevance of the discussed cell-level effects would be proven and, additionally, analgesic action of the opioid ingredient could be quantified.
Assuntos
Hormônio Liberador de Hormônio do Crescimento , Peptídeos Opioides , Humanos , Peptídeos Opioides/farmacologia , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Cicatrização , FibroblastosRESUMO
This paper is the forty-fourth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2021 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonizts and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Assuntos
Peptídeos Opioides , Receptores Opioides , Animais , Humanos , Peptídeos Opioides/farmacologia , Receptores Opioides/fisiologia , Analgésicos Opioides/farmacologia , Aprendizagem/fisiologia , Dor/tratamento farmacológicoRESUMO
Peptides have revealed a large range of biological activities with high selectivity and efficiency for the development of new drugs, including neuroprotective agents. Therefore, this work investigates the neuroprotective properties of naturally occurring peptides, endomorphin-1 (EM-1), endomorphin-2 (EM-2), rubiscolin-5 (R-5), and rubiscolin-6 (R-6). We aimed at answering the question of whether well-known opioid peptides can counteract cell injury in a common in vitro model of Parkinson's disease (PD). Antioxidant activity of these four peptides was evaluated by the 2-diphenyl-1-picrylhydrazyl radical (DPPH) scavenging activity, oxygen radical absorbance capacity (ORAC), and ferric-reducing antioxidant power (FRAP) assays, while neuroprotective effects were assessed in a neurotoxic model induced by 6-hydroxydopamine (6-OHDA) in a human neuroblastoma cell line (SH-SY5Y). The mechanisms associated with neuroprotection were investigated by the determination of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, and Caspase-3 activity. Among the tested peptides, endomorphins significantly prevented neuronal death induced by 6-OHDA treatment, decreasing MMP (EM-1) or Caspase-3 activity (EM-2). Meanwhile, R-6 showed antioxidant potential by FRAP assay and exhibited the highest capacity to recover the neurotoxicity induced by 6-OHDA via attenuation of ROS levels and mitochondrial dysfunction. Generally, we hypothesize that peptides' ability to suppress the toxic effect induced by 6-OHDA may be mediated by different cellular mechanisms. The protective effect caused by endomorphins results in an antiapoptotic effect (mitochondrial protection and decrease in Caspase-3 activity), while R-6 potency to increase a cell's viability seems to be mediated by reducing oxidative stress. Our results may provide new insight into neurodegeneration and support the short peptides as a potent drug candidate to treat PD. However, further studies should be conducted on the detailed mechanisms of how tested peptides could suppress neuronal injuries.
Assuntos
Neuroblastoma , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Doença de Parkinson , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Neuroblastoma/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Peptídeos Opioides/farmacologia , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
We tested the hypothesis that N/OFQ neurones in the arcuate nucleus (N/OFQARC ) inhibit proopiomelanocortin (POMCARC ) neurones in a diet- and hormone-dependent manner to promote a more extensive rebound hyperphagia upon re-feeding following an 18 h fast. We utilized intact male or ovariectomized (OVX) female mice subjected to ad libitum-feeding or fasting conditions. N/OFQARC neurones under negative energy balance conditions displayed heightened sensitivity as evidenced by a decreased rheobase threshold, increased firing frequency, and increased burst duration and frequency compared to ad libitum-feeding conditions. Stimulation of N/OFQARC neurones more robustly inhibited POMCARC neurones under fasting conditions compared to ad libitum-feeding conditions. N/OFQARC inhibition of POMCARC neurones is hormone dependent as chemostimulation of N/OFQARC neurones from fasted males and OVX females produced a sizable outward current in POMCARC neurones. Oestradiol (E2 ) markedly attenuated the N/OFQ-induced POMCARC outward current. Additionally, N/OFQ tonically inhibits POMCARC neurones to a greater degree under fasting conditions than in ad libitum-feeding conditions as evidenced by the abrogation of N/OFQ-nociceptin opioid peptide (NOP) receptor signalling and inhibition of N/OFQ release via chemoinhibition of N/OFQARC neurones. Intra-arcuate nucleus application of N/OFQ further elevated the hyperphagic response and increased meal size during the 6 h re-feed period, and these effects were mimicked by chemostimulation of N/OFQARC neurones in vivo. E2 attenuated the robust N/OFQ-induced rebound hyperphagia seen in vehicle-treated OVX females. These data demonstrate that N/OFQARC neurones play a vital role in mitigating the impact of negative energy balance by inhibiting the excitability of anorexigenic neural substrates, an effect that is diminished by E2 in females. KEY POINTS: Nociceptin/orphanin FQ (N/OFQ) promotes increased energy intake and decreased energy expenditure under conditions of positive energy balance in a sex- and hormone-dependent manner. Here it is shown that under conditions of negative energy balance, i.e. fasting, N/OFQ inhibits anorexigenic proopiomelanocortin (POMC) neurones to a greater degree compared to homeostatic conditions due to fasting-induced hyperexcitability of N/OFQ neurones. Additionally, N/OFQ promotes a sustained increase in rebound hyperphagia and increase in meal size during the re-feed period following a fast. These results promote greater understanding of how energy balance influences the anorexigenic circuitry of the hypothalamus, and aid in understanding the neurophysiological pathways implicated in eating disorders promoting cachexia.
Assuntos
Estradiol , Pró-Opiomelanocortina , Masculino , Feminino , Camundongos , Animais , Pró-Opiomelanocortina/metabolismo , Estradiol/farmacologia , Peptídeos Opioides/farmacologia , Peptídeos Opioides/metabolismo , Metabolismo Energético , Hiperfagia , NociceptinaRESUMO
Rubiscolin6 is a foodderived opioid peptide found in Spinacia oleracea that has antinociceptive, memoryenhancing, anxiolyticlike and antidepressant effects. Rubiscolin6 has been reported to have two opposing effects on food intake. Food intake is closely connected to gut motility; however, to the best of our knowledge, the effect of rubiscolin6 on gut motility has not been reported. The present study aimed to investigate the effect of rubiscolin6 on postprandial motility of the gastric antrum in conscious mice. A catheter was implanted in the gastric antrum of male C57BL/6J mice. Manometric measurements were performed in fasted male mice and chow was then provided to assess motility in the fed state. Rubiscolin6, the δopioid receptor antagonist naltrindole, a mixture of rubiscolin6 and naltrindole, or vehicle was administered intraperitoneally 30 min after eating. The percentage motor index (%MI) was then calculated. Cumulative food intake was measured in both ad libitumfed and overnightfasted mice. The %MI was significantly lower in mice treated with rubiscolin6 compared with that in the other groups, but normalized by treatment with the rubiscolin6/naltrindole mixture. The decrease in %MI induced by rubiscolin6 remained for 1 h after administration. Cumulative food intake was significantly higher 4 and 6 h after rubiscolin6 administration in ad libitumfed mice but was normalized by the rubiscolin6/naltrindole mixture. Food intake 30 min after rubiscolin6 administration was normal, but was higher in mice treated with the rubiscolin6/naltrindole mixture. Thus, rubiscolin6 may have a rapid effect to reduce postprandial antral motility and may subsequently increase food intake after this inhibitory effect disappears. These effects were revealed to be mediated through δopioid receptors. The orexigenic effect of rubiscolin6 may be applicable to the treatment of anorexia and cachexia.
Assuntos
Ansiolíticos , Antro Pilórico , Animais , Ansiolíticos/farmacologia , Ingestão de Alimentos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas de Entorpecentes/farmacologia , Peptídeos Opioides/farmacologia , Fragmentos de Peptídeos , Receptores Opioides , Ribulose-Bifosfato CarboxilaseRESUMO
Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs are being marketed thanks to new synthetic strategies for optimizing metabolism and alternative routes of administration. This tutorial review briefly introduces the history and role of natural opioid peptides and highlights the key findings on their structure-activity relationships for the opioid receptors. It discusses details on opioid peptidomimetics applied to develop therapeutic candidates for the treatment of pain from the pharmacological and structural points of view. The main focus is the current status of various mimetic tools and the successful applications summarized in tables and figures.
Assuntos
Peptídeos Opioides , Peptidomiméticos , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Descoberta de Drogas , Peptídeos Opioides/química , Peptídeos Opioides/farmacologia , Peptídeos Opioides/uso terapêutico , Peptidomiméticos/farmacologia , Peptidomiméticos/uso terapêutico , Receptores OpioidesRESUMO
This paper is the forty-third consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2020 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 (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Assuntos
Peptídeos Opioides , Receptores Opioides , Analgésicos Opioides/farmacologia , Animais , Feminino , Aprendizagem/fisiologia , Peptídeos Opioides/farmacologia , Dor/tratamento farmacológico , Gravidez , Receptores Opioides/agonistasRESUMO
RATIONALE AND OBJECTIVE: One objective of the National Institutes of Health Helping to End Addiction Long-term (HEAL) initiative is to accelerate research on safer and more effective medications for both pain and opioid use disorder. Ligands that activate the nociceptin opioid peptide receptor (NOP) constitute one class of candidate drugs for both applications. The present preclinical study determined the effectiveness of the NOP agonist Ro 64-6198 to produce antinociception in a pain-depressed behavior procedure and attenuate opioid self-administration in a heroin-vs-food choice procedure. METHODS: In Experiment 1, Adult Sprague-Dawley rats were equipped with microelectrodes and trained to respond for electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. The potency, time course, and receptor mechanism of effects produced by R0 64-6198 alone (0.32-3.2 mg/kg) on ICSS were examined, followed by evaluation of 0.32-1.0 mg/kg Ro 64-6198 effectiveness to block lactic acid-induced depression of ICSS. In Experiment 2, rats self-administered heroin under a heroin-vs-food choice procedure during a regimen of repeated, daily intraperitoneal administration of vehicle or Ro 64-6198 (1-3.2 mg/kg/day). RESULTS: Ro 64-6198 produced dose- and time-dependent ICSS depression that was blocked by the selective NOP antagonist SB612111 but not by naltrexone. Ro 64-6198 failed to block acid-induced depression of ICSS. Repeated Ro 64-6198 pretreatment also failed to attenuate heroin-vs-food choice up to doses that significantly decreased operant behavior. CONCLUSIONS: These results do not support the utility of Ro 64-6198 as a stand-alone medication for either acute pain or opioid use disorder.
Assuntos
Dor Aguda , Heroína , Imidazóis/farmacologia , Peptídeos Opioides/agonistas , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Compostos de Espiro/farmacologia , Dor Aguda/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Peptídeos Opioides/farmacologia , Ratos , Ratos Sprague-Dawley , NociceptinaRESUMO
Over the past two decades, opioid abuse has risen especially among women. In both sexes hippocampal neural circuits involved in associative memory formation and encoding of motivational incentives are critically important in the transition from initial drug use to drug abuse/dependence. Opioid circuits, particularly the mossy fiber pathway, are crucial for associative memory processes important for addiction. Our anatomical studies, especially those utilizing electron microscopic immunocytochemistry, have provided unique insight into sex differences in the distribution of opioid peptides and receptors in specific hippocampal circuits and how these distributions are altered following stress and oxycodone-associative learning processes. Here we review the hippocampal opioid system in rodents with respect to ovarian hormones effects and baseline sex differences then sex differences following acute and chronic stress. Next, we review sex differences in the hippocampal opioid system in unstressed and chronically stressed rats following oxycodone conditioned place preference. We show that opioid peptides and receptors are distributed within hippocampal circuits in females with elevated estrogen states in a manner that would enhance sensitivity to endogenous and exogenous opioids. Moreover, chronic stress primes the opioid system in females in a manner that would promote opioid-associative learning processes. In contrast, chronic stress has limited effects on the opioid system in males and reduces its capacity to support opioid-mediated learning processes. Interestingly, acute stress appears to prime males for opioid associative learning. On a broader scale the findings highlighted in this review have important implications in understanding sex differences in opioid drug use and abuse.
Assuntos
Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/metabolismo , Oxicodona/farmacologia , Receptores Opioides/metabolismo , Estresse Psicológico/metabolismo , Analgésicos Opioides/farmacologia , Animais , Condicionamento Clássico , Feminino , Hipocampo/metabolismo , Masculino , Microscopia Eletrônica/métodos , Neurônios/metabolismo , Peptídeos Opioides/farmacologia , Ratos , Receptores de Estrogênio/metabolismo , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Caracteres SexuaisRESUMO
Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as tolerance, addiction, respiratory depression, and cardiovascular events. This, in turn, can result in their overuse in cases of addiction, the need for dose escalation in cases of developing tolerance, and the emergence of dose-related opioid toxicity, resulting in respiratory depression or cardiovascular problems that can even lead to unintentional death. Therefore, a very important challenge for researchers is to look for ways to counteract the side effects of opioids. The use of peptides and their related compounds, which have been shown to modulate the effects of opioids, may provide such an opportunity. This short review is a compendium of knowledge about the most important and recent findings regarding selected peptides and their modulatory effects on various opioid actions, including cardiovascular and respiratory responses. In addition to the peptides more commonly reported in the literature in the context of their pro- and/or anti-opioid activity-such as neuropeptide FF (NPFF), cholecystokinin (CCK), and melanocyte inhibiting factor (MIF)-we also included in the review nociceptin/orphanin (N/OFQ), ghrelin, oxytocin, endothelin, and venom peptides.
Assuntos
Analgésicos Opioides/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Peptídeos/uso terapêutico , Analgésicos Opioides/farmacologia , Animais , Colecistocinina/farmacologia , Colecistocinina/uso terapêutico , Tolerância a Medicamentos , Grelina/farmacologia , Grelina/uso terapêutico , Humanos , Antagonistas de Entorpecentes/farmacologia , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Peptídeos Opioides/farmacologia , Peptídeos Opioides/uso terapêutico , Peptídeos/farmacologia , Receptores Opioides/metabolismo , NociceptinaRESUMO
Opioids play crucial roles in the regulation of many important brain functions including pain, memory, and neurogenesis. Activation of opioid receptors is reported to have neuroprotective effects after ischemic reperfusion injury. The objective of this study was to understand the role of biphalin and nociceptin, opioid receptor agonists, on blood-brain barrier (BBB) integrity during ischemic stroke. In this study, we aimed to measure the effect of biphalin and nociceptin on astrocytic glutamate uptake and on expression of excitatory amino acid transporter to study the indirect role of astrocytes on opioid receptor-mediated BBB protection during in vitro stroke conditions. We used mouse brain endothelial cells (bEnd.3) and primary astrocytes as an in vitro BBB model. Restrictive BBB properties were evaluated by measuring [14C] sucrose paracellular permeability and the redistribution of the tight junction proteins. The protective effect of biphalin and nociceptin on BBB integrity was assessed after exposing cells to oxygen glucose deprivation (OGD) and glutamate. It was observed that combined stress (2 mM glutamate and 2 hours of OGD) significantly reduced glutamate uptake by astrocytes; however, biphalin and nociceptin treatment increased glutamate uptake in primary astrocytes. This suggests a role of increased astrocytic buffering capacity in opioid-meditated protection of the BBB during ischemic stroke. It was also found that the combined stress significantly increased [14C] sucrose paracellular permeability in an in vitro BBB model. Biphalin and nociceptin treatment attenuated the effect of the combined stress, which was reversed by the opioid receptor antagonists, suggesting the role of opioid receptors in biphalin and nociception's BBB modulatory activity. SIGNIFICANT STATEMENT: There is an unmet need for discovering new efficacious therapeutic agents to offset the deleterious effects of ischemic stroke. Given the confirmed roles of opioid receptors in the regulation of central nervous system functions, opioid receptor agonists have been studied as potential neuroprotective options in ischemic conditions. This study adds to the knowledge about the cerebrovascular protective effects of opioid receptor agonists and provides insight about the mechanism of action of these agents.