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BACKGROUND: Opioid administration to patients with obstructive sleep apnoea (OSA) is controversial because they are believed to be more sensitive to opioids. However, objective data on opioid effects in OSA are lacking. We tested the hypothesis that subjects with untreated OSA have increased sensitivity to opioids compared with subjects without OSA, or with OSA treated with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP). METHODS: This was a single-centre, prospective cohort study in subjects without OSA (n=20), with untreated OSA (n=33), or with treated OSA (n=21). OSA diagnosis was verified using type III (in-home) polysomnography. Subjects received a stepped-dose remifentanil infusion (target effect-site concentrations of 0.5, 1, 2, 3, 4 ng ml-1). Primary outcome was miosis (pupil area fractional change), the most sensitive opioid effect. Secondary outcomes were ventilatory rate, end-expired CO2, sedation, and thermal analgesia. RESULTS: There were no differences in miosis between untreated OSA subjects (mean=0.51, 95% confidence interval [CI] 0.41-0.61) and subjects without OSA (mean=0.49, 95% CI 0.36-0.62) (mean difference=0.02, 95% CI -0.18 to 0.22); between treated OSA subjects (mean=0.56, 95% CI 0.43-0.68) and subjects without OSA (difference=0.07, 95% CI -0.16 to 0.29); or between untreated OSA and treated OSA (difference=-0.05, 95% CI -0.25 to 0.16). There were no significant differences between subjects without OSA, untreated OSA, and treated OSA in ventilatory rate, end-expired CO2, sedation, or thermal analgesia responses to remifentanil. There was no relationship between OSA severity and magnitude of opioid effects. CONCLUSIONS: Neither obstructive sleep apnoea nor obstructive sleep apnoea treatment affected sensitivity to the miotic, sedative, analgesic, or respiratory depressant effects of the opioid remifentanil in awake adults. These results challenge conventional notions of opioid effects in obstructive sleep apnoea. CLINICAL TRIAL REGISTRATION: NCT02898792 (clinicaltrials.gov).
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Analgésicos Opioides , Apneia Obstrutiva do Sono , Adulto , Humanos , Remifentanil/uso terapêutico , Estudos Prospectivos , Dióxido de Carbono , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/terapia , Dor , Miose/complicações , Pressão Positiva Contínua nas Vias Aéreas/métodosRESUMO
BACKGROUND: Adolescent Idiopathic Scoliosis (AIS) affects 2%-4% of the general pediatric population. While surgical correction remains one of the most common orthopedic procedures performed in pediatrics, limited consensus exists on the perioperative anesthetic management. AIMS: To examine the current state of anesthetic management of typical AIS spine fusions at institutions which have a dedicated pediatric orthopedic spine surgeon. METHODS: A web-based survey was sent to all members of the North American Pediatric Spine Anesthesiologists (NAPSA) Collaborative. This group included 34 anesthesiologists at 19 different institutions, each of whom has a Harms Study Group surgeon performing spine fusions at their hospital. RESULTS: Thirty-one of 34 (91.2%) anesthesiologists completed the survey, with a missing response rate from 0% to 16.1% depending on the question. Most anesthesia practices (77.4%; 95% confidence interval [CI], 67.7-93.4) do not have patients come for a preoperative visit prior to the day of surgery. Intravenous induction was the preferred method (74.2%; 95% CI 61.3-89.9), with the majority utilizing two peripheral IVs (93.5%; 95% CI 90.3-100) and an arterial line (100%; 95% CI 88.8-100). Paralytic administration for intubation and/or exposure was divided (51.6% rocuronium/vecuronium, 45.2% no paralytic, and 3.2% succinylcholine) amongst respondents. While tranexamic acid was consistently utilized for reducing blood loss, dosing regimens varied. When faced with neuromonitoring signal issues, 67.7% employ a formal protocol. Most anesthesiologists (93.5%; 95% CI 78.6-99.2) extubate immediately postoperatively with patients admitted to an inpatient floor bed (77.4%; 95% CI 67.7-93.3). CONCLUSION: Most anesthesiologists (87.1%; 95% CI 80.6-99.9) report the use of some form of an anesthesia-based protocol for AIS fusions, but our survey results show there is considerable variation in all aspects of perioperative care. Areas of agreement on management comprise the typical vascular access required, utilization of tranexamic acid, immediate extubation, and disposition to a floor bed. By recognizing the diversity of anesthetic care, we can develop areas of research and improve the perioperative management of AIS.
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Anestesiologistas , Escoliose , Fusão Vertebral , Humanos , Escoliose/cirurgia , Fusão Vertebral/métodos , Adolescente , Anestesia/métodos , Inquéritos e Questionários , América do NorteRESUMO
AIMS: Methadone metabolism and clearance are determined principally by polymorphic cytochrome P4502B6 (CYP2B6). Some CYP2B6 allelic variants affect methadone metabolism in vitro and disposition in vivo. We assessed methadone metabolism by CYP2B6 minor variants in vitro. We also assessed the influence of CYP2B6 variants, and P450 oxidoreductase (POR) and CYP2C19 variants, on methadone clearance in surgical patients in vivo. METHODS: CYP2B6 and P450 oxidoreductase variants were coexpressed with cytochrome b5 . The metabolism of methadone racemate and enantiomers was measured at therapeutic concentrations and intrinsic clearances were determined. Adolescents receiving methadone for surgery were genotyped for CYP2B6, CYP2C19 and POR, and methadone clearance and metabolite formation clearance were determined. RESULTS: In vitro, CYP2B6.4 was more active than wild-type CYP2B6.1. CYPs 2B6.5, 2B6.6, 2B6.7, 2B6.9, 2B6.17, 2B6.19 and 2B6.26 were less active. CYPs 2B6.16 and 2B6.18 were inactive. CYP2B6.1 expressed with POR variants POR.28, POR.5 and P228L had lower rates of methadone metabolism than wild-type reductase. In vivo, methadone clinical clearance decreased linearly with the number of CYP2B6 slow metabolizer alleles, but was not different in CYP2C19 slow or rapid metabolizer phenotypes, or in carriers of the POR*28 allele. CONCLUSIONS: Several CYP2B6 and POR variants were slow metabolizers of methadone in vitro. Polymorphisms in CYP2B6, but not CYP2C19 or P450 reductase, affected methadone clearance in vivo. CYP2B6 polymorphisms 516G>T and 983T>C code for canonical loss of function variants and should be assessed when considering genetic influences on clinical methadone disposition. These complementary translational in vitro and in vivo results inform on pharmacogenetic variability affecting methadone disposition in patients.
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Metadona , Farmacogenética , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2B6/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Citocromos bRESUMO
BACKGROUND: Opioids are a mainstay of perioperative analgesia. Opioid use in children with obstructive sleep apnea is challenging because of assumptions for increased opioid sensitivity and assumed risk for opioid-induced respiratory depression compared to children without obstructive sleep apnea. These assumptions have not been rigorously tested. This investigation tested the hypothesis that children with obstructive sleep apnea have an increased pharmacodynamic sensitivity to the miotic and respiratory depressant effects of the prototypic µ-opioid agonist remifentanil. METHODS: Children (8 to 14 yr) with or without obstructive sleep apnea were administered a 15-min, fixed-rate remifentanil infusion (0.05, 0.1, or 0.15 µg · kg · min). Each dose group had five patients with and five without obstructive sleep apnea. Plasma remifentanil concentrations were measured by tandem liquid chromatography mass spectrometry. Remifentanil effects were measured via miosis, respiratory rate, and end-expired carbon dioxide. Remifentanil pharmacodynamics (miosis vs. plasma concentration) were compared in children with or without obstructive sleep apnea. RESULTS: Remifentanil administration resulted in miosis in both non-obstructive sleep apnea and obstructive sleep apnea patients. No differences in the relationship between remifentanil concentration and miosis were seen between the two groups at any of the doses administered. The administered dose of remifentanil did not affect respiratory rate or end-expired carbon dioxide in either group. CONCLUSIONS: No differences in the remifentanil concentration-miosis relation were seen in children with or without obstructive sleep apnea. The dose and duration of remifentanil administered did not alter ventilatory parameters in either group.
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Analgésicos Opioides/administração & dosagem , Miose/induzido quimicamente , Miose/fisiopatologia , Remifentanil/administração & dosagem , Apneia Obstrutiva do Sono/fisiopatologia , Adolescente , Criança , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Masculino , Miose/diagnóstico , Apneia Obstrutiva do Sono/tratamento farmacológico , Apneia Obstrutiva do Sono/cirurgiaAssuntos
Filtros de Ar/efeitos adversos , Anestesia Geral/efeitos adversos , Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Serviços Médicos de Emergência/métodos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Anestesia Geral/instrumentação , COVID-19 , Infecções por Coronavirus/transmissão , Humanos , Hipercapnia/diagnóstico , Hipercapnia/etiologia , Pneumonia Viral/transmissão , Fatores de Risco , SARS-CoV-2 , Fatores de TempoRESUMO
Opioid overdose accounts for nearly 75,000 deaths per year in the United States, representing a leading cause of mortality amongst the prime working age population (25-54 years). At overdose levels, opioid-induced respiratory depression becomes fatal without timely administration of the rescue drug naloxone. Currently, overdose survival relies entirely on bystander intervention, requiring a nearby person to discover and identify the overdosed individual, and have immediate access to naloxone to administer. Government efforts have focused on providing naloxone in abundance but do not address the equally critical component for overdose rescue: a willing and informed bystander. To address this unmet need, we developed the Naloximeter: a class of life-saving implantable devices that autonomously detect and treat overdose, with the ability to simultaneously contact first-responders. We present three Naloximeter platforms, for both fundamental research and clinical translation, all equipped with optical sensors, drug delivery mechanisms, and a supporting ecosystem of technology to counteract opioid-induced respiratory depression. In small and large animal studies, the Naloximeter rescues from otherwise fatal opioid overdose within minutes. This work introduces life-changing, clinically translatable technologies that broadly benefit a susceptible population recovering from opioid use disorder.
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Regional anesthesia between the pectoralis major and minor was first described in 2011 as an alternative method to paravertebral blocks or epidurals for post-operative mastectomies. Since then, the use of pectoral nerve (PECS) blocks for post-operative pain management following thoracotomy, sternotomy, and other procedures in the anterior thorax has increased. While experience with this block is growing, the current understanding of its use in pediatric patients is limited. We reviewed pediatric cases at a single institution and provide a descriptive account of our use of PECS I and II blocks for post-operative pain management following operations involving sternotomy in pediatric patients. We performed a retrospective database analysis of the use of PECS I and II blocks following procedures requiring sternotomy from 2018 to 2021 at St. Louis Children's Hospital. Patients 21 years old and younger who received either a PECS I or II block following a sternotomy for a cardiac procedure were included in the analysis. Patient's demographics, pre-, intra-, and post-operative medications, operative time, extubation status, pain evaluations, and hospital course were assessed from the electronic medical record. From 2018 to 2021, 73 ultrasound-guided PECS blocks were performed for pain relief for pediatric sternotomy. The most commonly performed operations were atrial septal defect closure (n = 12), mitral valve repair (n = 8), and ventricle septal defect closure (n = 8). Out of the 73 patients, 47 received a PECS I block and 26 received a PECS II Block. 70 of the blocks were administered after closure of the sternum while 3 were done before incision. The time to perform blocks took on average of 6 (±4) min. Mean operating room time was 7.5 h. Local anesthetics used for the blocks were as follows: Ropivacaine 0.2% (n = 54), Ropivacaine 0.5% (n = 18), and Bupivacaine 0.25% (n = 1). Twenty-five out of 73 patients did not experience severe pain, defined as ≥7/10 on a numeric pain scale, at any point in the first 24 h following surgery. We describe the of use PECS I and II nerve block following pediatric sternotomy. Blocks were straight forward to perform, and typically took a short amount of time to administer (6 min), when compared to the total operating room time (7.5 h). While this study did not include a comparative group that did not receive a block, 34 percent of patients did not suffer from severe pain in the first 24 h following surgery. Further prospective studies are needed to assess the effectiveness of PECS blocks for pain relief following sternotomy in pediatric patients when compared to current standard of care. PECS blocks may be beneficial for a range of cardiac surgeries that typically result in severe postoperative pain.
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BACKGROUND: Mechanical ventilators are essential to patients who become critically ill with acute respiratory distress syndrome (ARDS), and shortages have been reported due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We utilized 3D printing (3DP) technology to rapidly prototype and test critical components for a novel ventilator multiplexer system, Vent-Lock, to split one ventilator or anesthesia gas machine between two patients. FloRest, a novel 3DP flow restrictor, provides clinicians control of tidal volumes and positive end expiratory pressure (PEEP), using the 3DP manometer adaptor to monitor pressures. We tested the ventilator splitter circuit in simulation centers between artificial lungs and used an anesthesia gas machine to successfully ventilate two swine. RESULTS: As one of the first studies to demonstrate splitting one anesthesia gas machine between two swine, we present proof-of-concept of a de novo, closed, multiplexing system, with flow restriction for potential individualized patient therapy. CONCLUSIONS: While possible, due to the complexity, need for experienced operators, and associated risks, ventilator multiplexing should only be reserved for urgent situations with no other alternatives. Our report underscores the initial design and engineering considerations required for rapid medical device prototyping via 3D printing in limited resource environments, including considerations for design, material selection, production, and distribution. We note that optimization of engineering may minimize 3D printing production risks but may not address the inherent risks of the device or change its indications. Thus, our case report provides insights to inform future rapid prototyping of medical devices.
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The central nucleus of the amygdala (CeA) has been identified as a site of nociceptive processing important for sensitization induced by peripheral injury. However, the cellular signaling components underlying this function remain unknown. Here, we identify metabotropic glutamate receptor 5 (mGluR5) as an integral component of nociceptive processing in the CeA. Pharmacological activation of mGluRs with (R,S)-3,5-dihydroxyphenylglycine (DHPG) in the CeA of mice is sufficient to induce peripheral hypersensitivity in the absence of injury. DHPG-induced peripheral hypersensitivity is reduced via pharmacological blockade of mGluR5 or genetic disruption of mGluR5. Furthermore, pharmacological blockade or conditional deletion of mGluR5 in the CeA abrogates inflammation-induced hypersensitivity, demonstrating the necessity of mGluR5 in CeA-mediated pain modulation. Moreover, we demonstrate that phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2) is downstream of mGluR5 activation in the CeA and is necessary for the full expression of peripheral inflammation-induced behavioral sensitization. Finally, we present evidence of right hemispheric lateralization of mGluR5 modulation of amygdalar nociceptive processing. We demonstrate that unilateral pharmacological activation of mGluR5 in the CeA produces distinct behavioral responses depending on whether the right or left amygdala is injected. We also demonstrate significantly higher levels of mGluR5 expression in the right amygdala compared with the left under baseline conditions, suggesting a potential mechanism for right hemispheric lateralization of amygdala function in pain processing. Together, these results establish an integral role for mGluR5 and ERK1/2 in nociceptive processing in the CeA.
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Tonsila do Cerebelo/metabolismo , Dor/fisiopatologia , Receptores de Ácido Caínico/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Análise de Variância , Animais , Butadienos/farmacologia , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Formaldeído , Lateralidade Funcional , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Hiperalgesia/metabolismo , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Nitrilas/farmacologia , Dor/induzido quimicamente , Dor/genética , Medição da Dor/métodos , Piridinas/farmacologia , Receptores de Glucocorticoides/deficiência , Receptores de Ácido Caínico/deficiênciaRESUMO
Group II metabotropic glutamate receptors (mGluRs) couple to the inhibitory G-protein Gi. The group II mGluRs include two subtypes, mGlu2 and mGlu3, and their pharmacological activation produces analgesic effects in inflammatory and neuropathic pain states. However, the specific contribution of each one of the two subtypes has not been clarified due to the lack of selective orthosteric ligands that can discriminate between mGlu2 and mGlu3 subtypes.In this study we used mGlu2 or mGlu3 knock-out mice to dissect the specific role for these two receptors in the endogenous control of inflammatory pain and their specific contribution to the analgesic activity of mixed mGlu2/3 receptor agonists.Our results showed that mGlu2â»(/)â» mice display a significantly greater pain response compared to their wild type littermates. Interestingly the increased pain sensitivity in mGlu2â»(/)â» mice occurred only in the second phase of the formalin test. No differences were observed in the first phase. In contrast, mGlu3â»(/)â» mice did not significantly differ from their wild type littermates in either phase of the formalin test.When systemically injected, a single administration of the mGlu2/3 agonist, LY379268 (3 mg/kg, ip), showed a significant reduction of both phases in wild-type mice and in mGlu3â»(/)â» but not in mGlu2â»(/)â» mice. However tolerance to the analgesic effect of LY379268 (3 mg/kg, ip) in mGlu3â»(/)â» mice developed following 5 consecutive days of injection.Taken together, these results demonstrate that: (i) mGlu2 receptors play a predominant role over mGlu3 receptors in the control of inflammatory pain in mice; (ii) the analgesic activity of mixed mGlu2/3 agonists is entirely mediated by the activation of the mGlu2 subtype and (iii) the development of tolerance to the analgesic effect of mGlu2/3 agonists develops despite the lack of mGlu3 receptors.
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Aminoácidos/farmacologia , Analgésicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inflamação/patologia , Dor/patologia , Receptores de Glutamato Metabotrópico/agonistas , Aminoácidos/administração & dosagem , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Relação Dose-Resposta a Droga , Inflamação/complicações , Inflamação/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Dor/complicações , Dor/fisiopatologia , Medição da Dor , Receptores de Glutamato Metabotrópico/deficiência , Receptores de Glutamato Metabotrópico/metabolismo , Teste de Desempenho do Rota-RodRESUMO
BACKGROUND: The metabotropic glutamate receptor 5 noncompetitive antagonist fenobam is analgesic in rodents. Future development of fenobam as an analgesic in humans will require a favorable long-term treatment profile and a lack of significant deleterious side effects. This study aimed to determine whether tolerance to fenobam's analgesic effects developed over 14 days and to assess for side effects in mice. METHODS: Mouse models of pain, locomotor behavior, and coordination were used. Fenobam or vehicle (n = 8 or 11 per group) was administered for 14 days, and analgesic tolerance to fenobam was assessed using the formalin test. Histopathologic examination, hematology, and clinical chemistry analysis after 14-day fenobam administration were also assessed (n = 12 or 9). The effects of fenobam on locomotor activity were assessed in the open field and elevated zero maze (n = 8 or 7). Coordination was assessed using ledge crossing and vertical pole descent tasks (n = 11 or 10). RESULTS: Tolerance to fenobam's analgesic effect did not develop after 14 days. Chronic fenobam administration resulted in statistically significantly less weight gain compared with vehicle control subjects, but did not cause any physiologically or statistically significant hematologic abnormalities, altered organ function, or abnormal histopathology of the liver, brain, or testes. Fenobam administration resulted in a metabotropic glutamate receptor 5-dependent increase in exploratory behavior but does not impair motor coordination at analgesic doses. CONCLUSIONS: Analgesic tolerance to repeat fenobam dosing does not develop. Chronic dosing of up to 14 days is well tolerated. Fenobam represents a promising candidate for the treatment of human pain conditions.
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Analgésicos/farmacologia , Tolerância a Medicamentos , Imidazóis/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Analgésicos/sangue , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Imidazóis/sangue , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Dor/tratamento farmacológico , Medição da Dor , Receptor de Glutamato Metabotrópico 5 , Aumento de Peso/efeitos dos fármacosRESUMO
INTRODUCTION: The relative power of slow-delta oscillations in the electroencephalogram (EEG), termed slow-wave activity (SWA), correlates with level of unconsciousness. Acoustic enhancement of SWA has been reported for sleep states, but it remains unknown if pharmacologically induced SWA can be enhanced using sound. Dexmedetomidine is a sedative whose EEG oscillations resemble those of natural sleep. This pilot study was designed to investigate whether SWA can be enhanced using closed-loop acoustic stimulation during sedation (CLASS) with dexmedetomidine. METHODS: Closed-Loop Acoustic Stimulation during Sedation with Dexmedetomidine (CLASS-D) is a within-subject, crossover, controlled, interventional trial with healthy volunteers. Each participant will be sedated with a dexmedetomidine target-controlled infusion (TCI). Participants will undergo three CLASS conditions in a multiple crossover design: in-phase (phase-locked to slow-wave upslopes), anti-phase (phase-locked to slow-wave downslopes) and sham (silence). High-density EEG recordings will assess the effects of CLASS across the scalp. A volitional behavioral task and sequential thermal arousals will assess the anesthetic effects of CLASS. Ambulatory sleep studies will be performed on nights immediately preceding and following the sedation session. EEG effects of CLASS will be assessed using linear mixed-effects models. The impacts of CLASS on behavior and arousal thresholds will be assessed using logistic regression modeling. Parametric modeling will determine differences in sleepiness and measures of sleep homeostasis before and after sedation. RESULTS: The primary outcome of this pilot study is the effect of CLASS on EEG slow waves. Secondary outcomes include the effects of CLASS on the following: performance of a volitional task, arousal thresholds, and subsequent sleep. DISCUSSION: This investigation will elucidate 1) the potential of exogenous sensory stimulation to potentiate SWA during sedation; 2) the physiologic significance of this intervention; and 3) the connection between EEG slow-waves observed during sleep and sedation.
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Metabotropic glutamate receptor 5 (mGlu5) has been shown to modulate nociception in animals, but no mGlu5 antagonists have been developed commercially as analgesics. The mGlu5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was originally evaluated for development as a nonbenzodiazepine anxiolytic. Fenobam is analgesic in numerous mouse pain models, acting exclusively through mGlu5 blockade. Furthermore, fenobam showed no signs of analgesic tolerance with up to 2 weeks of daily dosing in mice. Analgesic effects of fenobam in humans have not been reported. The purpose of this investigation was to evaluate fenobam pharmacokinetics and analgesic effects in humans. We first evaluated single-dose oral fenobam disposition in a parallel-group dose-escalation study in healthy volunteers. A second investigation tested the analgesic effects of fenobam in an established experimental human pain model of cutaneous sensitization using capsaicin cream and heat, in a double-blind placebo-controlled study. The primary outcome measure was the area of hyperalgesia and allodynia around the area applied with heat/capsaicin. Secondary outcome measures included nociception, measured as pain rating on a visual analog scale, heat pain detection threshold, and effects on cognition and mood. Fenobam plasma exposures showed considerable interindividual variability and were not linear with dose. Fenobam reduced sensitization vs placebo at a single timepoint (peak plasma concentration); we found no other difference between fenobam and placebo. Our results suggest highly variable fenobam disposition and minimal analgesic effects at the dose tested. We suggest that future studies testing analgesic effects of mGlu5 blockade are warranted, but such studies should use molecules with improved pharmacokinetic profiles.
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Analgésicos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hiperalgesia/tratamento farmacológico , Imidazóis/farmacologia , Dor/tratamento farmacológico , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Adulto , Analgésicos/farmacocinética , Analgésicos/uso terapêutico , Método Duplo-Cego , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Voluntários Saudáveis , Humanos , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Medição da Dor , Resultado do Tratamento , Adulto JovemRESUMO
Metabotropic glutamate receptor subtype 5 (mGlu5) has been demonstrated to play a role in the modulation of numerous nociceptive modalities. When administered via peripheral, intrathecal, or systemic routes, mGlu5 antagonists have analgesic properties in a variety of preclinical pain models. Despite a wealth of data supporting the use of mGlu5 antagonists to treat pain, studies have been limited to preclinical animal models due to a lack of mGlu5 antagonists that are approved for use in humans. It has been demonstrated previously that fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], an anxiolytic shown to be safe and effective in human trials, is a selective and potent noncompetitive antagonist of mGlu5 (J Pharmacol Exp Ther 315:711-721, 2005). Here, we report a series of studies aimed at testing whether fenobam, similar to the prototypical mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has analgesic properties in mice. We show that fenobam reduces formalin-induced pain behaviors and relieves established inflammation-induced thermal hypersensitivity in mice. Similar results were seen with MPEP. Administration of fenobam resulted in an increase in locomotor activity in the open-field task but did not impair performance on the accelerating Rotarod. Analysis of brain and plasma fenobam levels indicated that fenobam is rapidly concentrated in brain after intraperitoneal administration in mice but is essentially cleared from circulation within 1 h after injection. Fenobam had no analgesic effect in mGlu5 knockout mice, whereas the prototypical antagonist MPEP retained significant analgesic efficacy in mGlu5 knockouts. These results demonstrate that fenobam is analgesic in mice and has an improved in vivo selectivity for mGlu5 over MPEP.
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Analgésicos não Narcóticos , Imidazóis/farmacologia , Piridinas/farmacologia , Receptores de Ácido Caínico/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Calibragem , Cromatografia Líquida de Alta Pressão , Formaldeído , Adjuvante de Freund , Temperatura Alta , Imidazóis/farmacocinética , Indicadores e Reagentes , Inflamação/induzido quimicamente , Inflamação/complicações , Inflamação/patologia , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Dor/tratamento farmacológico , Dor/etiologia , Medição da Dor/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Controle de QualidadeRESUMO
Monitoring regional tissue oxygenation in animal models and potentially in human subjects can yield insights into the underlying mechanisms of local O2-mediated physiological processes and provide diagnostic and therapeutic guidance for relevant disease states. Existing technologies for tissue oxygenation assessments involve some combination of disadvantages in requirements for physical tethers, anesthetics, and special apparatus, often with confounding effects on the natural behaviors of test subjects. This work introduces an entirely wireless and fully implantable platform incorporating (i) microscale optoelectronics for continuous sensing of local hemoglobin dynamics and (ii) advanced designs in continuous, wireless power delivery and data output for tether-free operation. These features support in vivo, highly localized tissue oximetry at sites of interest, including deep brain regions of mice, on untethered, awake animal models. The results create many opportunities for studying various O2-mediated processes in naturally behaving subjects, with implications in biomedical research and clinical practice.
Assuntos
Fontes de Energia Elétrica , Oximetria/instrumentação , Próteses e Implantes , Tecnologia sem Fio/instrumentação , Animais , Substitutos Sanguíneos/análise , Corpo Estriado/metabolismo , Corpo Estriado/cirurgia , Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Oxigênio/análise , Ratos , Ratos Sprague-Dawley , Materiais InteligentesRESUMO
BACKGROUND: A number of prostaglandins (PGs) sensitize dorsal root ganglion (DRG) neurons and contribute to inflammatory hyperalgesia by signaling through specific G protein-coupled receptors (GPCRs). One mechanism whereby PGs sensitize these neurons is through modulation of "thermoTRPs," a subset of ion channels activated by temperature belonging to the Transient Receptor Potential ion channel superfamily. Acrid, electrophilic chemicals including cinnamaldehyde (CA) and allyl isothiocyanate (AITC), derivatives of cinnamon and mustard oil respectively, activate thermoTRP member TRPA1 via direct modification of channel cysteine residues. RESULTS: Our search for endogenous chemical activators utilizing a bioactive lipid library screen identified a cyclopentane PGD2 metabolite, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), as a TRPA1 agonist. Similar to CA and AITC, this electrophilic molecule is known to modify cysteines of cellular target proteins. Electophysiological recordings verified that 15d-PGJ2 specifically activates TRPA1 and not TRPV1 or TRPM8 (thermoTRPs also enriched in DRG). Accordingly, we identified a population of mouse DRG neurons responsive to 15d-PGJ2 and AITC that is absent in cultures derived from TRPA1 knockout mice. The irritant molecules that activate TRPA1 evoke nociceptive responses. However, 15d-PGJ2 has not been correlated with painful sensations; rather, it is considered to mediate anti-inflammatory processes via binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma). Our in vivo studies revealed that 15d-PGJ2 induced acute nociceptive responses when administered cutaneously. Moreover, mice deficient in the TRPA1 channel failed to exhibit such behaviors. CONCLUSION: In conclusion, we show that 15d-PGJ2 induces acute nociception when administered cutaneously and does so via a TRPA1-specific mechanism.
Assuntos
Canais de Cálcio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nociceptores/metabolismo , Medição da Dor , Prostaglandina D2/análogos & derivados , Fenômenos Fisiológicos da Pele , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Células CHO , Canais de Cálcio/fisiologia , Células Cultivadas , Cricetinae , Cricetulus , Gânglios Espinais/fisiologia , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/fisiologia , Nociceptores/fisiologia , Prostaglandina D2/fisiologia , Ratos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Fenômenos Fisiológicos da Pele/genética , Canal de Cátion TRPA1 , Canais de Potencial de Receptor Transitório/deficiência , Canais de Potencial de Receptor Transitório/fisiologiaRESUMO
Many GABAergic drugs are in clinical use as anesthetics, sedatives, or anxiolytics. We have investigated the actions of the combinations of the neuroactive steroid 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) with the intravenous anesthetic propofol or the benzodiazepine diazepam. The goal of the study was to determine whether coapplication of alfaxalone reduces the effective doses and concentrations of propofol and diazepam. Behavioral effects of alfaxalone, propofol, diazepam, and the combinations of the drugs were evaluated during a 30-min activity test in mice. Functional effects of the individual drugs and drug combinations were tested by measuring the decay times of spontaneous inhibitory postsynaptic currents in rat hippocampal neurons, and peak current responses from heterologously expressed concatemeric α1ß2γ2L GABAA receptors. Co-administration of alfaxalone increased the sedative actions of propofol and diazepam in mice. The combination of alfaxalone with propofol or diazepam increased the decay times of sIPSCs and shifted the concentration-response relationships for GABA-activated receptors to lower transmitter concentrations. We infer that alfaxalone acts as a co-agonist to enhance the GABAergic effects of propofol and diazepam. We propose that co-administration of alfaxalone, and possibly other neuroactive steroids, can be employed to reduce dosage requirements for propofol and diazepam.