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1.
Am J Vet Res ; 81(10): 775-782, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32969733

RESUMO

OBJECTIVE: To evaluate the thermal antinociceptive effects of hydromorphone hydrochloride after IM administration to orange-winged Amazon parrots (Amazona amazonica). ANIMALS: 8 healthy adult parrots (4 males and 4 females). PROCEDURES: In a randomized crossover study, each bird received hydromorphone (0.1, 1, and 2 mg/kg) and saline (0.9% NaCl) solution (1 mL/kg; control) IM, with a 7-day interval between treatments. Each bird was assigned an agitation-sedation score, and the thermal foot withdrawal threshold (TFWT) was measured at predetermined times before and after treatment administration. Adverse effects were also monitored. The TFWT, agitation-sedation score, and proportion of birds that developed adverse effects were compared among treatments over time. RESULTS: Compared with the mean TFWT for the control treatment, the mean TFWT was significantly increased at 0.5, 1.5, and 3 hours and 1.5, 3, and 6 hours after administration of the 1- and 2-mg/kg hydromorphone doses, respectively. Significant agitation was observed at 0.5, 1.5, and 3 hours after administration of the 1 - and 2-mg/kg hydromorphone doses. Other adverse effects observed after administration of the 1- and 2-mg/kg doses included miosis, ataxia, and nausea-like behavior (opening the beak and moving the tongue back and forth). CONCLUSIONS AND CLINICAL RELEVANCE: Although the 1- and 2-mg/kg hydromorphone doses appeared to have antinociceptive effects, they also caused agitation, signs of nausea, and ataxia. Further research is necessary to evaluate administration of lower doses of hydromorphone and other types of stimulation to better elucidate the analgesic and adverse effects of the drug in psittacine species.


Assuntos
Amazona , Analgésicos Opioides , Hidromorfona , Analgésicos , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Animais , Estudos Cross-Over , Feminino , Hidromorfona/efeitos adversos , Hidromorfona/farmacologia , Masculino
2.
Mol Pharmacol ; 98(5): 548-558, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32913138

RESUMO

The prototypical member of the receptor-inactivating kappa opioid receptor (KOR) antagonists, norbinaltorphimine (norBNI), produces prolonged receptor inactivation by a cJun kinase mechanism. These antagonists have potential therapeutic utility in the treatment of stress disorders; however, additional preclinical characterization is necessary to understand important aspects of their action. In this study, we report that norBNI does not work as effectively in female mice as in males because of estrogen regulation of G protein receptor kinase (GRK); pretreatment of ovary-intact female mice with the selective GRK2/3 inhibitor, Compound 101, made females equally sensitive to norBNI as males. Prior observations suggested that in vivo treatment with norBNI does not produce long-lasting inhibition of KOR regulation of dopamine release in the nucleus accumbens. We assessed the persistence of norBNI receptor inactivation in subcellular compartments. Fast-scan cyclic voltammetry recordings confirmed that presynaptic inhibition of dopamine release by the KOR agonist U69,593 was not blocked by in vivo pretreatment with norBNI under conditions that prevented KOR-mediated aversion and analgesia. We employed a novel in vivo proxy sensor of KOR activation, adenovirus associated double floxed inverted-HyPerRed, and demonstrated that KOR activation stimulates cJun kinase-dependent reactive oxygen species (ROS) production in somatic regions of ventral tegmental area dopamine neurons, but did not activate ROS production in dopamine terminals. The compartment selective action helps explain how dopamine somatic, but not terminally expressed, KORs are inactivated by norBNI. These results further elucidate molecular signaling mechanisms mediating receptor-inactivating KOR antagonist action and advance medication development for this novel class of stress-resilience medications. SIGNIFICANCE STATEMENT: Kappa opioid receptor (KOR) antagonists are being developed as novel proresilience therapeutics for the treatment of mood and substance use disorders. This study showed that the long-acting KOR antagonists are affected by both the sex of the animal and the subcellular compartment in which the receptor is expressed.


Assuntos
Antagonistas de Entorpecentes/farmacologia , Receptores Opioides kappa/metabolismo , Analgésicos Opioides/farmacologia , Animais , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
PLoS One ; 15(9): e0239094, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915912

RESUMO

The G protein-gated inwardly rectifying K+ (GIRK) channels play important signaling roles in the central and peripheral nervous systems. However, the role of GIRK channel activation in pain signaling remains unknown mainly due to the lack of potent and selective GIRK channel activators until recently. The present study was designed to determine the effects and mechanisms of ML297, a selective GIRK1/2 activator, on nociception in the spinal cord by using behavioral studies and whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurons. Rats were prepared for chronic lumber catheterization and intrathecal administration of ML297. The nociceptive flexion reflex was tested using an analgesy-meter, and the influence on motor performance was assessed using an accelerating rotarod. We also investigated pre- and post-synaptic actions of ML297 in spinal cord preparations by whole-cell patch-clamp recordings. Intrathecal administration of ML297 increased the mechanical nociceptive threshold without impairing motor function. In voltage-clamp mode of patch-clamp recordings, bath application of ML297 induced outward currents in a dose-dependent manner. The ML297-induced currents demonstrated specific equilibrium potential like other families of potassium channels. At high concentration, ML297 depressed miniature excitatory postsynaptic currents (mEPSCs) but not their amplitude. The ML297-induced outward currents and suppression of mEPSCs were not inhibited by naloxone, a µ-opioid receptor antagonist. These results demonstrated that intrathecal ML297 showed the antinociceptive effect, which was mediated through direct activation of pre- and post-synaptic GIRK channels. Selective GIRK channel activation is a promising strategy for the development of new agents against chronic pain and opioid tolerance.


Assuntos
Analgésicos/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/agonistas , Nociceptividade/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Pirazóis/farmacologia , Substância Gelatinosa/efeitos dos fármacos , Analgésicos/uso terapêutico , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Animais , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Dor Crônica/tratamento farmacológico , Tolerância a Medicamentos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Humanos , Injeções Espinhais , Masculino , Modelos Animais , Naloxona/administração & dosagem , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Nociceptividade/fisiologia , Técnicas de Patch-Clamp , Compostos de Fenilureia/uso terapêutico , Pirazóis/uso terapêutico , Ratos , Substância Gelatinosa/citologia , Substância Gelatinosa/fisiologia
4.
Mol Pharmacol ; 98(4): 462-474, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32958572

RESUMO

Opioid receptors (ORs) convert extracellular messages to signaling events by coupling to the heterotrimeric G proteins, Gα•ßγ Classic pharmacological methods, such as [35S]GTPγS binding and inhibition of cyclic AMP production, allow for general opioid characterization, but they are subject to the varying endogenous Gα proteins in a given cell type. Bioluminescence resonance energy transfer (BRET) technology offers new insight by allowing the direct observation of Gα subunit-specific effects on opioid pharmacology. Using a Venus-tagged Gßγ and nanoluciferase-tagged truncated G protein receptor kinase 3, an increase in BRET signal correlated with OR activation mediated by a specific Gα protein. The magnitude of the BRET signal was normalized to the maximum response obtained with 10 µM 2-(3,4-dichlorophenyl)-N-methyl-N-[(1R,2R)-2-pyrrolidin-1-ylcyclohexyl]acetamide (U50,488) for the kappa OR (KOR). Opioids reached equilibrium with the KOR, and concentration-response curves were generated. Although the full agonists U50,488, salvinorin A, nalfurafine, and dynorphin peptides were equally efficacious regardless of the Gα subunit present, the concentration-response curves were leftward shifted when the KOR was signaling through Gαz compared with other Gαi/o subunits. In contrast, the Gα subunit distinctly affected both the efficacy and potency of partial kappa agonists, such as the benzomorphans, and the classic mu opioid antagonists, naloxone, naltrexone, and nalmefene. For example, (-)pentazocine had EC50 values of 7.3 and 110 nM and maximal stimulation values of 79% and 35% when the KOR signaled through Gαz and Gαi1, respectively. Together, these observations suggest KOR pharmacology varies based on the specific Gα subunit coupled to the KOR. SIGNIFICANCE STATEMENT: Opioid receptors couple to various heterotrimeric Gαßγ proteins to convert extracellular cues to precise intracellular events. This paper focuses on how the various inhibitory Gα subunits influence the pharmacology of full and partial agonists at the kappa opioid receptor. Using a bioluminescent assay, the efficacy and potency of kappa opioids was determined. Opioid signaling was more potent through Gαz compared with other Gα proteins. These observations suggest that Gαz may impact opioid pharmacology and cellular physiology more than previously thought.


Assuntos
Analgésicos Opioides/farmacologia , Técnicas de Transferência de Energia por Ressonância de Bioluminescência/métodos , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Receptores Opioides kappa/metabolismo , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Diterpenos Clerodânicos/farmacologia , Dinorfinas/farmacologia , Células HEK293 , Humanos , Morfinanos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/farmacologia
5.
Mol Pharmacol ; 98(4): 433-444, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32958571

RESUMO

For decades the broad role of opioids in addiction, neuropsychiatric disorders, and pain states has been somewhat well established. However, in recent years, with the rise of technological advances, not only is the existing dogma being challenged, but we are identifying new disease areas in which opioids play a critical role. This review highlights four new areas of exploration in the opioid field. The most recent addition to the opioid family, the nociceptin receptor system, shows promise as the missing link in understanding the neurocircuitry of motivation. It is well known that activation of the kappa opioid receptor system modulates negative affect and dysphoria, but recent studies now implicate the kappa opioid system in the modulation of negative affect associated with pain. Opioids are critical in pain management; however, the often-forgotten delta opioid receptor system has been identified as a novel therapeutic target for headache disorders and migraine. Lastly, changes to the gut microbiome have been shown to directly contribute to many of the symptoms of chronic opioid use and opioid related behaviors. This review summarizes the findings from each of these areas with an emphasis on identifying new therapeutic targets. SIGNIFICANCE STATEMENT: The focus of this minireview is to highlight new disease areas or new aspects of disease in which opioids have been implicated; this includes pain, motivation, migraine, and the microbiome. In some cases, this has resulted in the pursuit of a novel therapeutic target and resultant clinical trial. We believe this is very timely and will be a refreshing take on reading about opioids and disease.


Assuntos
Analgésicos Opioides/farmacologia , Transtornos de Enxaqueca/metabolismo , Transtornos Relacionados ao Uso de Opioides/microbiologia , Dor/metabolismo , Receptores Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Motivação , Transtornos Relacionados ao Uso de Opioides/metabolismo , Dor/tratamento farmacológico , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Am Surg ; 86(9): 1153-1158, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32812770

RESUMO

BACKGROUND: Pain control is an important aspect of rib fracture management. With a rise in multimodal care approaches, we hypothesized that transdermal lidocaine patches reduce opioid utilization in hospitalized patients with acute rib fractures not requiring continuous opioid infusion. METHODS: We performed a retrospective analysis of adult trauma patients with acute rib fractures admitted to the Trauma Service from January 2011 to October 2018. We compared patients who received transdermal lidocaine patches to those who did not and evaluated cumulative opioid consumption, expressed in morphine milligram equivalents (MMEs). Secondary outcomes included the rate of pulmonary complications and length of hospital stay. RESULTS: Of the 21 190 trauma admissions, 3927 (18.5%) had rib fractures. Overall, 1555 patients who received continuous opioid infusion were excluded. Of the remaining 2372 patients, 725 (30.6%) patients received lidocaine patches. The mean total MME of patients who received lidocaine patches was 55.7 MME (30.7 MME on multivariate analysis) and was lower than that of patients who did not receive lidocaine patches (P ≤ .01). There was no difference in hospital length of stay (no lidocaine patches vs received lidocaine patches: 6.2 days vs 6.5 days, P = .34) or pulmonary complications (1.7% vs 2.8%, P = .08). DISCUSSION: In admitted trauma patients with acute rib fractures not requiring continuous intravenous opiates, lidocaine patch use was associated with a significant decrease in opiate utilization during the patients' hospital course.


Assuntos
Analgésicos Opioides/farmacologia , Lidocaína/farmacologia , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Manejo da Dor/métodos , Fraturas das Costelas/terapia , Anestésicos Locais/farmacologia , Feminino , Humanos , Incidência , Masculino , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Estudos Retrospectivos , Estados Unidos/epidemiologia
7.
Anesthesiology ; 133(3): 559-568, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32788558

RESUMO

BACKGROUND: To improve understanding of the respiratory behavior of oliceridine, a µ-opioid receptor agonist that selectively engages the G-protein-coupled signaling pathway with reduced activation of the ß-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility. METHODS: Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers (n = 30) were reanalyzed. A population pharmacokinetic-pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia ≥ 0.5) - P(respiratory depression ≥ 0.25), where analgesia ≥ 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression ≥ 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median ± standard error of the estimate. RESULTS: The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 ± 4.9 ng/ml; morphine 34.3 ± 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 ± 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 ± 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P < 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia. CONCLUSIONS: These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range.


Assuntos
Analgésicos Opioides/farmacologia , Morfina/farmacologia , Insuficiência Respiratória/induzido quimicamente , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Adulto , Analgésicos Opioides/efeitos adversos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/efeitos adversos , Valores de Referência , Medição de Risco , Compostos de Espiro/efeitos adversos , Tiofenos/efeitos adversos , Adulto Jovem
8.
J S Afr Vet Assoc ; 91(0): e1-e8, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32787423

RESUMO

Potent opioids are known to cause negative alterations to the physiology of immobilised antelope. How these effects differ between species has not been studied. This study aimed to compare time to recumbence and effects of opioid-based immobilisation on the physiology of impala (Aepyceros melampus) and blesbok (Damaliscus pygargus phillipsi). Eight animals of each species were immobilised, with 0.09 mg/kg etorphine and 0.09 mg/kg thiafentanil respectively, in a randomised two-way cross-over study. Variables measured and analysed by means of a linear mixed model included time to recumbence, heart rate, respiratory rate, arterial blood pressure, blood gases, lactate and glucose. In blesbok, mean time to recumbence was not significantly different with either drug (2.5 minutes and 2.2 min, respectively), but in impala thiafentanil achieved a shorter time to recumbence (2.0 min) than etorphine (3.9 min). Mean heart rates of immobilised impala were within reported physiological limits, but lower in immobilised blesbok when both opioids were used (35 beats/min to 44 beats/min vs. 104 ± 1.4 beats/min resting heart rate). Impala developed severe respiratory compromise and hypoxaemia from both opioids (overall mean PaO2 values ranged from 38 mmHg to 59 mmHg over 30 min). In contrast, blesbok developed only moderate compromise. Therefore, significantly different species-specific physiological responses to potent opioid drugs exist in blesbok and impala. Given that these different responses are clinically relevant, extrapolation of immobilising drug effects from one species of African ungulate to another is not recommended.


Assuntos
Analgésicos Opioides/farmacologia , Antílopes/fisiologia , Etorfina/farmacologia , Fentanila/análogos & derivados , Hipnóticos e Sedativos/farmacologia , Imobilização/veterinária , Analgésicos Opioides/administração & dosagem , Animais , Estudos Cross-Over , Etorfina/administração & dosagem , Feminino , Fentanila/administração & dosagem , Fentanila/farmacologia , Hipnóticos e Sedativos/administração & dosagem , Distribuição Aleatória , Especificidade da Espécie
9.
Pediatrics ; 146(2)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32680879

RESUMO

OBJECTIVES: Cardiorespiratory and pulse oximetry monitoring in children who are hospitalized should balance benefits of detecting deterioration with potential harms of alarm fatigue. We developed recommendations for monitoring outside the ICU on the basis of available evidence and expert opinion. METHODS: We conducted a comprehensive literature search for studies addressing the utility of cardiorespiratory and pulse oximetry monitoring in common pediatric conditions and drafted candidate monitoring recommendations based on our findings. We convened a panel of nominees from national professional organizations with diverse expertise: nursing, medicine, respiratory therapy, biomedical engineering, and family advocacy. Using the RAND/University of California, Los Angeles Appropriateness Method, panelists rated recommendations for appropriateness and necessity in 3 sequential rating sessions and a moderated meeting. RESULTS: The panel evaluated 56 recommendations for intermittent and continuous monitoring for children hospitalized outside the ICU with 7 common conditions (eg, asthma, croup) and/or receiving common therapies (eg, supplemental oxygen, intravenous opioids). The panel reached agreement on the appropriateness of monitoring recommendations for 55 of 56 indications and on necessity of monitoring for 52. For mild or moderate asthma, croup, pneumonia, and bronchiolitis, the panel recommended intermittent vital sign or oximetry measurement only. The panel recommended continuous monitoring for severe disease in each respiratory condition as well as for a new or increased dose of intravenous opiate or benzodiazepine. CONCLUSIONS: Expert panel members agreed that intermittent vital sign assessment, rather than continuous monitoring, is appropriate management for a set of specific conditions of mild or moderate severity that require hospitalization.


Assuntos
Eletrocardiografia , Monitorização Fisiológica/métodos , Oximetria , Guias de Prática Clínica como Assunto , Transtornos Respiratórios/fisiopatologia , Testes de Função Respiratória , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacologia , Criança , Criança Hospitalizada , Técnica Delfos , Relação Dose-Resposta a Droga , Humanos , Oxigenoterapia , Respiração/efeitos dos fármacos , Transtornos Respiratórios/etiologia , Sepse/fisiopatologia
11.
Br J Anaesth ; 125(3): 267-274, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32660717

RESUMO

BACKGROUND: Anaesthetic agents are likely to alter circulating cytokine concentrations. Because preceding studies have not been able to exclude the contribution of surgical trauma, perioperative stress, or both to circulating cytokine concentrations, the effects of anaesthesia remain unclear. The aim of this study was to quantify serum cytokines in healthy volunteers administered i.v. anaesthetic agents in the absence of surgical trauma and perioperative stress. METHODS: Serum samples obtained during previous standardised studies from healthy volunteers were compared before and 6-8 h after induction of anaesthesia with propofol (n=31), propofol/remifentanil (n=30), dexmedetomidine (n=17) or dexmedetomidine/remifentanil (n=15). Anaesthetic regimens were standardised and volunteers did not undergo any surgical intervention. Serum concentrations of interleukin (IL)2, IL4, IL6, IL10, IL17, IL18, IL21, IL22, IL23, C-X-C motif ligand 8, interferon gamma, E-selectin, L-selectin, major histocompatibility complex class I chain-polypeptide-related sequence (MIC)A, MICB, Granzyme A, and Granzyme B were quantified using a multiplexed antibody-based assay (Luminex). RESULTS: Samples were obtained from volunteers of either sex aged 18-70 yr. After anaesthesia with propofol alone, concentrations of IL4 (P=0.012), IL6 (P=0.027), IL21 (P=0.035), IL22 (P=0.002), C-X-C motif ligand 8 (P=0.004), MICB (P=0.046), and Granzyme A (P=0.045) increased. After anaesthesia with propofol and remifentanil, IL17 (P=0.013), interferon gamma (P=0.003), and MICA (P=0.001) decreased, but IL6 (P=0.006) and L-selectin (P=0.001) increased. After dexmedetomidine alone, IL18 (P=0.002), L-selectin (P=0.017), E-selectin (P=0.002), and Granzyme B (P=0.023) decreased. After dexmedetomidine with remifentanil no changes were observed. CONCLUSIONS: In healthy volunteers not undergoing surgery, different i.v. anaesthesia regimens were associated with differential effects on circulating cytokines.


Assuntos
Citocinas/sangue , Citocinas/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Propofol/farmacologia , Remifentanil/farmacologia , Adolescente , Adulto , Idoso , Analgésicos Opioides/farmacologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Adulto Jovem
12.
Mol Pharmacol ; 98(4): 410-424, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32665252

RESUMO

Evidence from several novel opioid agonists and knockout animals suggests that improved opioid therapeutic window, notably for analgesia versus respiratory depression, is a result of ligand bias downstream of activation of the µ-opioid receptor (MOR) toward G protein signaling and away from other pathways, such as arrestin recruitment. Here, we argue that published claims of opioid bias based on application of the operational model of agonism are frequently confounded by failure to consider the assumptions of the model. These include failure to account for intrinsic efficacy and ceiling effects in different pathways, distortions introduced by analysis of amplified (G protein) versus linear (arrestin) signaling mechanisms, and nonequilibrium effects in a dynamic signaling cascade. We show on both theoretical and experimental grounds that reduced intrinsic efficacy that is unbiased across different downstream pathways, when analyzed without due considerations, does produce apparent but erroneous MOR ligand bias toward G protein signaling, and the weaker the G protein partial agonism is the greater the apparent bias. Experimentally, such apparently G protein-biased opioids have been shown to exhibit low intrinsic efficacy for G protein signaling when ceiling effects are properly accounted for. Nevertheless, such agonists do display an improved therapeutic window for analgesia versus respiratory depression. Reduced intrinsic efficacy for G proteins rather than any supposed G protein bias provides a more plausible, sufficient explanation for the improved safety. Moreover, genetic models of G protein-biased opioid receptors and replication of previous knockout experiments suggest that reduced or abolished arrestin recruitment does not improve therapeutic window for MOR-induced analgesia versus respiratory depression. SIGNIFICANCE STATEMENT: Efforts to improve safety of µ-opioid analgesics have focused on agonists that show signaling bias for the G protein pathway versus other signaling pathways. This review provides theoretical and experimental evidence showing that failure to consider the assumptions of the operational model can lead to large distortions and overestimation of actual bias. We show that low intrinsic efficacy is a major determinant of these distortions, and pursuit of appropriately reduced intrinsic efficacy should guide development of safer opioids.


Assuntos
Analgésicos Opioides/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Opioides mu/metabolismo , Animais , Humanos , Ligantes , Receptores Acoplados a Proteínas-G/agonistas , Transdução de Sinais/efeitos dos fármacos
13.
Mol Pharmacol ; 98(4): 475-486, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32680919

RESUMO

Methadone is a synthetic opioid agonist with notoriously unique properties, such as lower abuse liability and induced relief of withdrawal symptoms and drug cravings, despite acting on the same opioid receptors triggered by classic opioids-in particular the µ-opioid receptor (MOR). Its distinct pharmacologic properties, which have recently been attributed to the preferential activation of ß-arrestin over G proteins, make methadone a standard-of-care maintenance medication for opioid addiction. Although a recent biophysical study suggests that methadone stabilizes different MOR active conformations from those stabilized by classic opioid drugs or G protein-biased agonists, how this drug modulates the conformational equilibrium of MOR and what specific active conformation of the receptor it stabilizes are unknown. Here, we report the results of submillisecond adaptive sampling molecular dynamics simulations of a predicted methadone-bound MOR complex and compare them with analogous data obtained for the classic opioid morphine and the G protein-biased ligand TRV130. The model, which is supported by existing experimental data, is analyzed using Markov state models and transfer entropy analysis to provide testable hypotheses of methadone-specific conformational dynamics and activation kinetics of MOR. SIGNIFICANCE STATEMENT: Opioid addiction has reached epidemic proportions in both industrialized and developing countries. Although methadone maintenance treatment represents an effective therapeutic approach for opioid addiction, it is not as widely used as needed. In this study, we contribute an atomic-level understanding of how methadone exerts its unique function in pursuit of more accessible treatments for opioid addiction. In particular, we present details of a methadone-specific active conformation of the µ-opioid receptor that has thus far eluded experimental structural characterization.


Assuntos
Analgésicos Opioides/farmacologia , Metadona/farmacologia , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Analgésicos Opioides/química , Animais , Sítios de Ligação , Entropia , Humanos , Cadeias de Markov , Metadona/química , Camundongos , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Compostos de Espiro/química , Tiofenos/química
14.
Mol Pharmacol ; 98(4): 487-496, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32723769

RESUMO

Opioids are some of the most potent analgesics available. However, their effectiveness is limited by the development of analgesic tolerance. Traditionally, tolerance was thought to occur by termination of µ-opioid receptor (MOR) signaling via desensitization and internalization. Contradictory findings led to a more recent proposal that sustained MOR signaling caused analgesic tolerance. However, this view has also been called into question. We recently discovered that the platelet-derived growth factor receptor(PDGFR)-ß signaling system is both necessary and sufficient to cause opioid tolerance. We therefore propose a completely new hypothesis: that opioid tolerance is mediated by selective cellular signals and is independent of MOR internalization. To test this hypothesis, we developed an automated software-based method to perform unbiased analyses of opioid-induced MOR internalization in the rat substantia gelatinosa. We induced tolerance with either morphine, which did not cause MOR internalization, or fentanyl, which did. We also blocked tolerance by administering morphine or fentanyl with the PDGFR-ß inhibitor imatinib. We found that imatinib blocked tolerance without altering receptor internalization induced by either morphine or fentanyl. We also showed that imatinib blocked tolerance to other clinically used opioids. Our findings indicate that opioid tolerance is not dependent upon MOR internalization and support the novel hypothesis that opioid tolerance is mediated by intracellular signaling that can be selectively targeted. This suggests the exciting possibility that undesirable opioid side effects can be selectively eliminated, dramatically improving the safety and efficacy of opioids. SIGNIFICANCE STATEMENT: Classically, it was thought that analgesic tolerance to opioids was caused by desensitization and internalization of µ-opioid receptors (MORs). More recently, it was proposed that sustained, rather than reduced, MOR signaling caused tolerance. Here, we present conclusive evidence that opioid tolerance occurs independently of MOR internalization and that it is selectively mediated by platelet-derived growth factor receptor signaling. This novel hypothesis suggests that dangerous opioid side effects can be selectively targeted and blocked, improving the safety and efficacy of opioids.


Assuntos
Analgésicos Opioides/farmacologia , Tolerância a Medicamentos , Mesilato de Imatinib/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Opioides mu/metabolismo , Animais , Fentanila/farmacologia , Masculino , Modelos Animais , Morfina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Software
15.
Anesth Analg ; 131(3): 935-942, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32701545

RESUMO

BACKGROUND: The misuse of opioids stems, in part, from inadequate knowledge of molecular interactions between opioids and opioid receptors. It is still unclear why some opioids are far more addictive than others. The κ-opioid receptor (KOR) plays a critical role in modulating pain, addiction, and many other physiological and pathological processes. Butorphanol, an opioid analgesic, is a less addictive opioid with unique pharmacological profiles. In this study, we investigated the interaction between butorphanol and KOR to obtain insights into the safe usage of this medication. METHODS: We determined the binding affinity of butorphanol to KOR with a naltrexone competition study. Recombinant KORs expressed in mammalian cell membranes (Chem-1) were used for G-protein activation studies, and a human embryonic kidney-293 (HEK-293) cell line stably transfected with the human KOR was used for ß-arrestin study as previously described in the literature. The effects of butorphanol on KOR internalization were investigated using mouse neuroblastoma Neuro2A cells stably transfected with mKOR-tdTomato fusion protein (N2A-mKOR-tdT) cells overexpressing KOR. The active-state KOR crystal structure was used for docking calculation of butorphanol to characterize the ligand binding site. Salvinorin A, a full KOR agonist, was used as a control for comparison. RESULTS: The affinity of KOR for butorphanol is characterized by Kd of 0.1 ± 0.02 nM, about 20-fold higher compared with that of the µ-opioid receptor (MOR; 2.4 ± 1.2 nM). Our data indicate that butorphanol is more potent on KOR than on MOR. In addition, butorphanol acts as a partial agonist of KOR in the G-protein activation pathway and is a full agonist on the ß-arrestin recruitment pathway, similar to that of salvinorin A. The activation of the ß-arrestin pathway is further confirmed by KOR internalization. The in silico docking model indicates that both salvinorin A and butorphanol share the same binding cavity with the KOR full agonist MP1104. This cavity plays an important role in determining either agonist or antagonist effects of the ligand. CONCLUSIONS: In conclusion, butorphanol is a partial KOR agonist in the G-protein activation pathway and a potent KOR full agonist in the ß-arrestin recruitment pathway. The structure analysis offers insights into the molecular mechanism of KOR interaction and activation by butorphanol.


Assuntos
Analgésicos Opioides/farmacologia , Butorfanol/farmacologia , Neurônios/efeitos dos fármacos , Receptores Opioides kappa/agonistas , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Analgésicos Opioides/toxicidade , Animais , Butorfanol/química , Butorfanol/metabolismo , Butorfanol/toxicidade , Linhagem Celular Tumoral , Agonismo Parcial de Drogas , Células HEK293 , Humanos , Camundongos , Simulação de Acoplamento Molecular , Neurônios/metabolismo , Ligação Proteica , Conformação Proteica , Receptores Opioides kappa/química , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , beta-Arrestinas/metabolismo
16.
Curr Opin Anaesthesiol ; 33(4): 483-489, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32530894

RESUMO

PURPOSE OF REVIEW: Growing concerns about the environmental effects of volatile anaesthetics are likely to lead to increased use of intravenous anaesthetic drugs. Pharmacokinetic/pharmacodynamic (PKPD) models can increase the accuracy of intravenous drug titration, especially in populations that differ from the 'average.' However, with a growing number of PKPD models, and other technology available to date, it can be hard to see the wood for the trees. This review attempts to guide the reader through the PKPD jungle. RECENT FINDINGS: General purpose PKPD models for propofol and remifentanil designed to apply to a broader population, including children, the elderly and the obese, reduce the need for population-specific models. PKPD models for drugs such as dexmedetomidine and antimicrobial agents may be useful for procedural sedation or in the ICU. Technological advances such as Bayesian model adjustment based on point-of-care plasma concentration measurements, closed-loop drug delivery and artificial intelligence may improve the ease of use of the anaesthetic drugs and increase the accuracy of titration. SUMMARY: Newer and more complex modelling techniques and technological advancements can help to deliver anaesthetic drugs, sedatives and other drugs in a more stable and thereby safer way.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos Opioides/farmacocinética , Anestésicos/farmacologia , Anestésicos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/farmacocinética , Propofol/farmacologia , Propofol/farmacocinética , Remifentanil/farmacologia , Remifentanil/farmacocinética , Idoso , Anestesia , Anestésicos Intravenosos , Inteligência Artificial , Teorema de Bayes , Criança , Relação Dose-Resposta a Droga , Humanos , Modelos Biológicos
17.
PLoS One ; 15(6): e0234199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497141

RESUMO

INTRODUCTION: To mitigate the recent nationwide shortage of intravenous opioids, we developed a standardized perioperative oral opioid guideline anchored with appropriate use of nonopioid analgesia, neuraxial and loco-regional techniques. We hypothesize that adoption of this new guideline was associated with: 1) equivalent patient reported pain scores in the post-anesthesia care unit (PACU); and 2) equivalent total opioid use (oral and parenteral) during the perioperative period. METHODS: Cases performed from July 1, 2017 to May 31, 2019 were screened. All opioids administered were converted to intravenous morphine milligram equivalents. Segmented regression analyses of interrupted time series were performed examining the change in opioid use, PACU pain scores and number of non-opioid analgesic medications used before and after the protocol implementation in April 2018. RESULTS: After exclusions, 29, 621 cases were included in the analysis. No significant differences in demographic, ASA status, case length and surgical procedure type were present in the pre and post-intervention period. A significant decrease in total (Estimate: -39.9 mg, SE: 6.9 mg, p < 0.001) and parenteral (Estimate: -51.6 mg, SE: 7.1 mg, p < 0.001) opioid use with a significant increase in oral opioid use (Estimate: 9.4 mg, SE: 1.1 mg, p < 0.001) was noted after the intervention. Pain scores were not significantly different between the pre- and post-intervention period (Estimate: 0.05, SE: 0.13, p = 0.69). CONCLUSION: We report our experience with a primary perioperative oral based opioid regimen that is associated with decreased total opioid consumption and equivalent patient reported pain scores.


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Análise de Séries Temporais Interrompida , Período Perioperatório , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/provisão & distribução , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Adulto Jovem
18.
J Pharmacol Exp Ther ; 374(3): 376-391, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32513839

RESUMO

Synthetic opioids, including fentanyl and its analogs, have therapeutic efficacy in analgesia and anesthesia. However, their illicit use in the United States has increased and contributed to the number one cause of death for adults 18-50 years old. Fentanyl and the heroin metabolite morphine induce respiratory depression that can be treated with the µ opioid receptor (MOR) antagonist naloxone. With higher or more rapid dosing, fentanyl, more than morphine, causes chest wall rigidity and can also induce rapid onset laryngospasm. Because non-MORs could mediate differing clinical manifestations, we examined the interactions of fentanyl and morphine at recombinant human neurotransmitter transporters, G protein-coupled receptors, and the N-methyl-D-aspartate glutamate receptor. Both drugs were agonists at MOR, κ, and δ opioid receptors. Morphine had little or no affinity at other human receptors and transporters (K i or IC50 value >100 µM). However, fentanyl had K i values of 1407 and 1100 nM at α 1A and α 1B adrenoceptor subtypes, respectively, and K i values of 1049 and 1670 nM at dopamine D4.4 and D1 receptor subtypes, respectively; it also blocked [3H]neurotransmitter uptake by the vesicular monoamine transporter 2 (IC50 = 911 nM). Pharmacokinetic models indicate that these Ki and IC50 values are pharmacologically relevant. Fentanyl had little affinity for other receptors or transporters. Thus, noradrenergic disposition at specific receptor subtypes in relevant organs may play a role in respiratory and cardiothoracic effects of fentanyl. Data suggest that less selective fentanyl receptor pharmacology could play a role in the different clinical effects of morphine compared with fentanyl, including fentanyl-induced deaths after illicit use. SIGNIFICANCE STATEMENT: The synthetic opioid fentanyl induces different clinical effects, including rapid onset muscular rigidity, vocal cord closure, and rapid death, than the heroin metabolite morphine. Our data indicate for the first time that the two drugs have very different effects at recombinant human neurotransmitter receptors and transporters that might explain those clinical differences.


Assuntos
Analgésicos não Entorpecentes/farmacologia , Fentanila/farmacologia , Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Neurotransmissores/metabolismo , Analgésicos Opioides/farmacologia , Animais , Células CHO , Linhagem Celular , Cricetulus , Células HEK293 , Humanos , Naloxona/farmacologia , Ratos , Receptores de Neurotransmissores , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo
19.
Anesthesiology ; 133(3): 628-644, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32568844

RESUMO

BACKGROUND: Increased descending pain facilitation accounts for opioid-induced hyperalgesia, but the underlying mechanisms remain elusive. Given the role of µ-opioid receptors in opioid-induced hyperalgesia in animals, the authors hypothesized that the dorsal reticular nucleus, a medullary pain facilitatory area, is involved in opioid-induced hyperalgesia through altered µ-opioid receptor signaling. METHODS: The authors used male Wistar rats (n = 5 to 8 per group), chronically infused with morphine, to evaluate in the dorsal reticular nucleus the expressions of the µ-opioid receptor and phosphorylated cAMP response element-binding, a downstream marker of excitatory µ-opioid receptor signaling. The authors used pharmacologic and gene-mediated approaches. Nociceptive behaviors were evaluated by the von Frey and hot-plates tests. RESULTS: Lidocaine fully reversed mechanical and thermal hypersensitivity induced by chronic morphine. Morphine-infusion increased µ-opioid receptor, without concomitant messenger RNA changes, and phosphorylated cAMP response element-binding levels at the dorsal reticular nucleus. µ-opioid receptor knockdown in morphine-infused animals attenuated the decrease of mechanical thresholds and heat-evoked withdrawal latencies compared with the control vector (von Frey [mean ± SD]: -17 ± 8% vs. -40 ± 9.0%; P < 0.001; hot-plate: -10 ± 5% vs. -32 ± 10%; P = 0.001). µ-opioid receptor knockdown in control animals induced the opposite (von Frey: -31 ± 8% vs. -17 ± 8%; P = 0.053; hotplate: -24 ± 6% vs. -3 ± 10%; P = 0.001). The µ-opioid receptor agonist (D-ALA2,N-ME-PHE4,GLY5-OL)-enkephalin acetate (DAMGO) decreased mechanical thresholds and did not affect heat-evoked withdrawal latencies in morphine-infused animals. In control animals, DAMGO increased both mechanical thresholds and heat-evoked withdrawal latencies. Ultra-low-dose naloxone, which prevents the excitatory signaling of the µ-opioid receptor, administered alone, attenuated mechanical and thermal hypersensitivities, and coadministered with DAMGO, restored DAMGO analgesic effects and decreased phosphorylated cAMP response element-binding levels. CONCLUSIONS: Chronic morphine shifted µ-opioid receptor signaling from inhibitory to excitatory at the dorsal reticular nucleus, likely enhancing descending facilitation during opioid-induced hyperalgesia in the rat.


Assuntos
Analgésicos Opioides/farmacologia , Hiperalgesia/induzido quimicamente , Bulbo/efeitos dos fármacos , Morfina/farmacologia , Receptores Opioides mu/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
20.
J Pharmacol Exp Ther ; 374(3): 392-403, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32586850

RESUMO

Opioid use disorders (OUDs) and opioid-related fatal overdoses are a significant public health concern in the United States and worldwide. To offer more effective medical interventions to treat or prevent OUD, antiopioid vaccines are in development that reduce the distribution of the targeted opioids to brain and subsequently reduce the associated behavioral and toxic effects. It is of critical importance that antiopioid vaccines do not interfere with medications that treat OUD. Hence, this study tested the preclinical proof of concept of combining a candidate oxycodone vaccine [oxycodone-keyhole limpet hemocyanin (OXY-KLH)] with an FDA-approved extended-release naltrexone (XR-NTX) depot formulation in rats. The effects of XR-NTX on oxycodone-induced motor activity and antinociception were first assessed in nonvaccinated naïve rats to establish a baseline for subsequent studies. Next, OXY-KLH and XR-NTX were coadministered to determine whether the combination would affect the efficacy of each individual treatment, and it was found that the combination of OXY-KLH and XR-NTX offered greater efficacy in reducing oxycodone-induced motor activity, thigmotaxis, antinociception, and respiratory depression over a range of repeated or escalating oxycodone doses in rats. These data support the feasibility of combining antibody-based therapies with opioid receptor antagonists to provide greater or prolonged protection against opioid-related toxicity or overdose. Combining antiopioid vaccines with XR-NTX may provide prophylactic measures to subjects at risk of relapse and accidental or deliberate exposure. Combination therapy may extend to other biologics (e.g., monoclonal antibodies) and medications against substance use disorders. SIGNIFICANCE STATEMENT: Opioid use disorders (OUDs) remain a major problem worldwide, and new therapies are needed. This study reports on the combination of an oxycodone vaccine [oxycodone-keyhole limpet hemocyanin (OXY-KLH)] with a currently approved OUD therapy, extended-release naltrexone (XR-NTX). Results demonstrated that XR-NTX did not interfere with OXY-KLH efficacy, and combination of low doses of XR-NTX with vaccine was more effective than each individual treatment alone to reduce behavioral and toxic effects of oxycodone, suggesting that combining OXY-KLH with XR-NTX may improve OUD outcomes.


Assuntos
Preparações de Ação Retardada/farmacologia , Naltrexona/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Oxicodona/farmacologia , Vacinas/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Hemocianinas/farmacologia , Masculino , Antagonistas de Entorpecentes/farmacologia , Ratos
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