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Could pharmacogenetic data explain part of the interindividual sensitivity to methadone-induced respiratory depression?

Crettol, Séverine; Monnat, Martine; Eap, Chin B
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.27%
In this issue of Critical Care, Megarbane and colleagues present a case report of methadone-induced respiratory depression and conduct a toxicokinetic/toxicodynamic evaluation. An opioid-dependent patient receiving methadone maintenance treatment (daily dose 70 mg) was found unconscious after ingesting 240 mg methadone and 2 mg flunitrazepam. Significant improvement in consciousness was achieved after an intravenous bolus of 0.3 mg naloxone followed by a continuous infusion of naloxone at 0.3 mg/hour. In patients receiving methadone maintenance treatment, an occasional intake of two to four times the usual daily dose of methadone is not an exceptional occurrence. However, few such patients experience episodes of life-threatening respiratory depression. Here, we discuss whether recent pharmacogenetic data could help us to understand interindividual variability in sensitivity to respiratory depression and, ultimately, to predict which patients are most likely to be affected.

Measurement of Meperidine Induced Respiratory Depression Using a New Non-Invasive Technique

Hersh, Elliot V.; Desjardins, Paul J.; Simpser, Moises; Dadzie, Charles
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //1985 EN
Relevância na Pesquisa
46.27%
Inductive plethysmography was used to assess the magnitude and duration of respiratory depression caused by doses of meperidine commonly administered during dental intravenous sedation. Minute volume measurements exhibited a high degree of accuracy when compared to simultaneous spirometry. Intravenously administered meperidine 25 mg/70 kg and 50 mg/70 kg both caused a significant shift to the right in their respective ventilatory-pco2 response curves. The magnitude and duration of this respiratory depression was dose related. Even relatively low doses of meperidine used in dental intravenous sedation cause respiratory depression.

Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia

Hutchinson, Mark R.; Northcutt, Alexis L.; Chao, Lindsey W.; Kearney, Jeffrey J.; Zhang, Yingning; Berkelhammer, Debra L.; Loram, Lisa C.; Rozeske, Robert R.; Bland, Sondra T.; Maier, Steven F.; Gleeson, Todd T.; Watkins, Linda R.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.27%
Recent data suggest that opioids can activate immune-like cells of the central nervous system (glia). This opioid-induced glial activation is associated with decreased analgesia, owing to the release of proinflammatory mediators. Here we examine in rats whether the putative microglial inhibitor, minocycline, may affect morphine-induced respiratory depression and/or morphine-induced reward (conditioned place preference). Systemic co-administration of minocycline significantly attenuated morphine-induced reductions in tidal volume, minute volume, inspiratory force and expiratory force, but did not affect morphine-induced reductions in respiratory rate. Minocycline attenuation of respiratory depression was also paralleled with significant attenuation by minocycline of morphine-induced reductions in blood oxygen saturation. Minocycline also attenuated morphine conditioned place preference. Minocycline did not simply reduce all actions of morphine, as morphine analgesia was significantly potentiated by minocycline co-administration. Lastly, morphine dose-dependently increased cyclooxygenase-1 gene expression in a rat microglial cell line, an effect that was dose-dependently blocked by minocycline. Together, these data support that morphine can directly activate microglia in a minocycline-suppressible manner and suggest a pivotal role for minocycline-sensitive processes in the mechanisms of morphine-induced respiration depression...

S-Methadone augments R-methadone induced respiratory depression in the neonatal guinea pig

Silverman, Daniel A. N.; Nettleton, Rosemary T.; Spencer, Katherine B.; Wallisch, Michael; Olsen, George D.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.29%
Methadone is administered as a racemic mixture, although its analgesic and respiratory effects are attributed to R-isomer activity at the mu-opioid receptor (MOP). Recently, we observed a four-fold increase in inspiratory time in three-day old guinea pigs following an injection of racemic methadone. We hypothesized that this effect was due to augmentation of R-methadone induced respiratory depression by the S-methadone isomer. In the current longitudinal study, we injected three-, seven-, and fourteen-day old neonatal guinea pigs with saline, R-methadone, S-methadone, or R- plus S-methadone in order to characterize the roles of the individual isomers, as well as the synergistic effects of co-administration. Using plethysmography, we measured respiratory parameters while breathing room air and during a 5% CO2 challenge. S-methadone alone had no respiratory effects. However, the R- plus S-methadone group showed greater respiratory depression and increased inspiratory time than the R-methadone group in the youngest animals, suggesting that the respiratory effects of R-methadone are augmented by S-methadone in early development.

Respiratory depression during VP shunting in Arnold Chiari malformation Type-II, a rare complication (Case reports and review of literature)

Sahu, Sandeep; Lata, Indu; Srivastava, Vineet; Gupta, Davendra
Fonte: Medknow Publications Publicador: Medknow Publications
Tipo: Artigo de Revista Científica
Publicado em //2009 EN
Relevância na Pesquisa
46.18%
The VP Shunt is a common pediatric surgical procedure in our country. Hydrocephalus is commonly associated with meningomyelocele in Arnold Chiari malformation-II and the ventriculoperitoneal shunt insertion is the common surgical procedure for the management of hydrocephalus. The standard protocol is to rule out any hydrocephalus by preoperative MRI. If associated with hydrocephalus, insertion of the VP shunt is indicated before the repair of MMC whereas the absence of hydrocephalus indicates that the surgical repair of MMC is to be undertaken immediately. Anesthetic management of the patient during the insertion of ventriculoperitoneal shunt may pose problems. We report here two cases of ACM-II (lumbar MMC with associated hydrocephalus) who had respiratory depression / delayed emergence after an otherwise uneventful procedure. Although the VP shunt (first procedure) required postoperative ventilation which improved later, the phenomena of respiratory depression / delayed emergence did not occur after the MMC repair (second surgery). The possible mechanisms involved in these events and their various clinical aspects are discussed below.

Activation of Protein Kinase C (PKC)α or PKCε as an Approach to Increase Morphine Tolerance in Respiratory Depression and Lethal OverdoseS⃞

Lin, Hong-Yiou; Law, Ping-Yee; Loh, Horace H.
Fonte: The American Society for Pharmacology and Experimental Therapeutics Publicador: The American Society for Pharmacology and Experimental Therapeutics
Tipo: Artigo de Revista Científica
Publicado em /04/2012 EN
Relevância na Pesquisa
46.43%
Long-term use of opioids is hindered by respiratory depression and the possibility for fatal overdose in drug abusers. This is attributed to higher levels of tolerance that develops against antinociception than to respiratory depression. Identifying important mechanisms that would increase morphine respiratory depression and overdose tolerance could lead to the safer use of opioids. Because protein kinase C (PKC) activity mediates the development and maintenance of morphine antinociceptive tolerance, we hypothesized that activating PKCα or PKCε at the pre-Bötzinger complex (preBötC) can increase morphine tolerance in respiration and overdose. Laser microdissection and quantitative reverse transcriptase-polymerase chain reaction were used to compare the relative mRNA abundances of PKCα, γ, and ε between ventrolateral periaqueductal gray (vlPAG) and preBötC. To test whether PKCα or ε could enhance morphine tolerance in respiratory depression and overdose, lentivirus carrying the wild type, constitutively activated mutants, and small interference RNA against PKCα or ε was stereotaxically injected into the preBötC. Expression of constitutively active PKC (CAPKC) α or ε, but not wild-type PKC (WTPKC) α or ε, at the preBötC allowed rats to develop tolerance to morphine respiratory depression. In terms of lethality...

Aspiration Pneumonitis Caused by Delayed Respiratory Depression Following Intrathecal Morphine Administration

Whang, Bo Young; Jeong, Seong Whan; Leem, Jeong Gill; Kim, Young Ki
Fonte: The Korean Pain Society Publicador: The Korean Pain Society
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.22%
Opioid analgesia is the primary pharmacologic intervention for managing pain. However, opioids can cause various adverse effects including pruritus, nausea, constipation, and sedation. Respiratory depression is the most fatal side effect. Therefore, cautious monitoring of respiratory status must be done after opioid administration. Here, we report a patient who suffered from respiratory depression with deep sedation and aspiration pneumonitis after intrathecal morphine administration.

γ-Hydroxybutyrate (GHB)-Induced Respiratory Depression: Combined Receptor-Transporter Inhibition Therapy for Treatment in GHB Overdose

Morse, Bridget L.; Vijay, Nisha; Morris, Marilyn E.
Fonte: The American Society for Pharmacology and Experimental Therapeutics Publicador: The American Society for Pharmacology and Experimental Therapeutics
Tipo: Artigo de Revista Científica
Publicado em /08/2012 EN
Relevância na Pesquisa
46.43%
Overdose of γ-hydroxybutyrate (GHB) frequently causes respiratory depression, occasionally resulting in death; however, little is known about the dose-response relationship or effects of potential overdose treatment strategies on GHB-induced respiratory depression. In these studies, the parameters of respiratory rate, tidal volume, and minute volume were measured using whole-body plethysmography in rats administered GHB. Intravenous doses of 200, 600, and 1500 mg/kg were administered to assess the dose-dependent effects of GHB on respiration. To determine the receptors involved in GHB-induced respiratory depression, a specific GABAB receptor antagonist, (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), and a specific GABAA receptor antagonist, bicuculline, were administered before GHB. The potential therapeutic strategies of receptor inhibition and monocarboxylate transporter (MCT) inhibition were assessed by inhibitor administration 5 min after GHB. The primary effect of GHB on respiration was a dose-dependent decrease in respiratory rate, accompanied by an increase in tidal volume, resulting in little change in minute volume. Pretreatment with 150 mg/kg SCH50911 completely prevented the decrease in respiratory rate, indicating agonism at GABAB receptors to be primarily responsible for GHB-induced respiratory depression. Administration of 50 mg/kg SCH50911 after GHB completely reversed the decrease in respiratory rate; lower doses had partial effects. Administration of the MCT inhibitor l-lactate increased GHB renal and total clearance...

Respiratory depression following iatrogenic tramadol overuse in a patient with chronic renal failure

Mattia, Consalvo; Mazzaferro, Sandro; Coluzzi, Flaminia; Luzi, Marta
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
Publicado em /08/2004 EN
Relevância na Pesquisa
46.27%
We describe a case of tramadol-related respiratory depression in a 69-year-old man, admitted to our hospital because of severe anemia and melena in the context of chronic renal failure and dialysis treatment. He complained of back pain due to spondylodiscitis, and analgesic therapy was established with tramadol (200 mg/day intravenously). The patient received a total daily dose of 400 mg tramadol because of a therapeutic mistake. The patient tolerated this dosage for about two days before experiencing symptoms of opioid overdose that disappeared after naloxone treatment. In contrast with other opioids, few cases of tramadol-related respiratory depression have been described, in patients with impaired renal function, as tramadol is mainly excreted by kidneys. This case report emphasizes the need to avoid tramadol overuse in patients with renal failure, who could experience side effects such as respiratory depression.

Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717

Ren, Jun; Ding, Xiuqing; Greer, John J.
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.46%
Barbiturate use in conjunction with alcohol can result in severe respiratory depression and overdose deaths. The mechanisms underlying the additive/synergistic actions were unresolved. Current management of ethanol-barbiturate-induced apnea is limited to ventilatory and circulatory support coupled with drug elimination. Based on recent preclinical and clinical studies of opiate-induced respiratory depression, we hypothesized that ampakine compounds may provide a treatment for other types of drug-induced respiratory depression. The actions of alcohol, pentobarbital, bicuculline, and the ampakine CX717, alone and in combination, were measured via 1) ventral root recordings from newborn rat brain stem-spinal cord preparations and 2) plethysmographic recordings from unrestrained newborn and adult rats. We found that ethanol caused a modest suppression of respiratory drive in vitro (50 mM) and in vivo (2 g/kg ip). Pentobarbital induced an ∼50% reduction in respiratory frequency in vitro (50 μM) and in vivo (28 mg/kg for pups and 56 mg/kg for adult rats ip). However, severe life-threatening apnea was induced by the combination of the agents in vitro and in vivo via activation of GABAA receptors, which was exacerbated by hypoxic (8% O2) conditions. Administration of the ampakine CX717 alleviated a significant component of the respiratory depression in vitro (50–150 μM) and in vivo (30 mg/kg ip). Bicuculline also alleviated ethanol-/pentobarbital-induced respiratory depression but caused seizure activity...

Pain-facilitating medullary neurons contribute to opioid-induced respiratory depression

Phillips, Ryan S.; Cleary, Daniel R.; Nalwalk, Julia W.; Arttamangkul, Seksiri; Hough, Lindsay B.; Heinricher, Mary M.
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.38%
Respiratory depression is a therapy-limiting side effect of opioid analgesics, yet our understanding of the brain circuits mediating this potentially lethal outcome remains incomplete. Here we studied the contribution of the rostral ventromedial medulla (RVM), a region long implicated in pain modulation and homeostatic regulation, to opioid-induced respiratory depression. Microinjection of the μ-opioid agonist DAMGO in the RVM of lightly anesthetized rats produced both analgesia and respiratory depression, showing that neurons in this region can modulate breathing. Blocking opioid action in the RVM by microinjecting the opioid antagonist naltrexone reversed the analgesic and respiratory effects of systemically administered morphine, showing that this region plays a role in both the analgesic and respiratory-depressant properties of systemically administered morphine. The distribution of neurons directly inhibited by RVM opioid microinjection was determined with a fluorescent opioid peptide, dermorphin-Alexa 594, and found to be concentrated in and around the RVM. The non-opioid analgesic improgan, like DAMGO, produced antinociception but, unlike DAMGO, stimulated breathing when microinjected into the RVM. Concurrent recording of RVM neurons during improgan microinjection showed that this agent activated RVM ON-cells...

Opioid-induced respiratory depression: reversal by non-opioid drugs

van der Schier, Rutger; Roozekrans, Margot; van Velzen, Monique; Dahan, Albert; Niesters, Marieke
Fonte: Faculty of 1000 Ltd Publicador: Faculty of 1000 Ltd
Tipo: Artigo de Revista Científica
Publicado em 04/09/2014 EN
Relevância na Pesquisa
46.25%
The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality. One possible way of prevention of OIRD is by adding a respiratory stimulant to the opioid treatment, which through activation of non-opioidergic pathways will excite breathing and consequently will offset OIRD and should not affect analgesia. Various new respiratory stimulants are currently under investigation including (a) potassium channel blockers acting at the carotid bodies, and (b) ampakines and (c) serotonin receptor agonists acting within the brainstem. (a) GAL-021 targets BKCa-channels. Initial animal and human experimental evidence indicates that this potassium channel blocker is a potent respiratory stimulant that reverses OIRD without affecting antinociception. GAL021 is safe and better tolerated than the older K+-channel blocker doxapram and more efficacious in its effect on respiration. (b) Ampakines modulate glutamatergic respiratory neurons in brainstem respiratory centers. Various ampakines have been studied showing their ability to increase respiratory drive during OIRD by increasing respiratory rate. Currently...

Non-invasive respiratory volume monitoring identifies opioid-induced respiratory depression in an orthopedic surgery patient with diagnosed obstructive sleep apnea: a case report

Fleming, Eamon; Voscopoulos, Christopher; George, Edward
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
66.36%
Introduction: Obstructive sleep apnea and opioid-induced respiratory depression can unpredictably threaten respiratory competence in the post-anesthesia care unit. Current respiratory monitoring relies heavily on respiratory rate and oxygen saturation, as well as subjective clinical assessment. These assessments have distinct limitations, and none provide a real-time, objective, quantitative direct measurement of respiratory status. A novel, non-invasive respiratory volume monitor uses bioimpedance to provide accurate, quantitative measurements of minute ventilation, tidal volume and respiratory rate continuously in real time, providing a direct measurement of ventilation. Case presentation: The case describes an orthopedic surgery patient (54-year-old Caucasian man, body mass index 33.7kg/m2) with diagnosed obstructive sleep apnea in whom the respiratory volume monitor data depicted persistent apneic behavior undetected by other monitoring. The monitor was able to detect a sudden reduction in minute ventilation after initial opioid administration in the post-anesthesia care unit. The patient had sustained low minute ventilation until discharge. Neither respiratory rate data from the hospital monitor nor oxygen saturation readings reflected the respiratory decompensation...

Naloxone methiodide reverses opioid-induced respiratory depression and analgesia without withdrawal

Lewanowitsch, T.; Irvine, R.
Fonte: Elsevier Science BV Publicador: Elsevier Science BV
Tipo: Artigo de Revista Científica
Publicado em //2002 EN
Relevância na Pesquisa
46.35%
Illicit opioid overdoses are a significant problem throughout the world, with most deaths being attributed to opioid-induced respiratory depression which may involve peripheral mechanisms. The current treatment for overdoses is naloxone hydrochloride, which is effective but induces significant withdrawal. We propose that selectively peripherally acting opioid receptor antagonists, such as naloxone methiodide, could reverse respiratory depression without inducing predominantly centrally mediated withdrawal. Acute administration of morphine (300 mg/kg, i.p.) was found to significantly depress respiratory rate and induce analgesia (P<0.0001). Both naloxone hydrochloride and naloxone methiodide were able to reverse these effects but naloxone methiodide precipitated no significant withdrawal. Naloxone methiodide was also able to reverse opioid-induced respiratory depression (P<0.001) and antinociception (P<0.01) after chronic morphine administration (300 mg/kg/day for 5 days) without inducing significant withdrawal. Therefore, peripherally selective opioid receptor antagonists should be investigated as possible treatments for opioid-induced respiratory depression which do not induce adverse effects, such as withdrawal.; http://www.elsevier.com/wps/find/journaldescription.cws_home/506087/description#description; Tanya Lewanowitsch and Rodney J. Irvine; Copyright © 2002 Elsevier Science B.V. All rights reserved.

Use of radiotelemetry to evaluate respiratory depression produced by chronic methadone administration

Lewanowitsch, T.; White, J.; Irvine, R.
Fonte: Elsevier Science BV Publicador: Elsevier Science BV
Tipo: Artigo de Revista Científica
Publicado em //2004 EN
Relevância na Pesquisa
66.31%
Illicit and therapeutic opioid administration can result in overdose due to opioid-induced respiratory depression. Research investigating the respiratory depressant effects of opioids has been limited due to difficulties associated with acquiring long-term respiratory data. This study examined the novel use of radiotelemetry to measure respiratory rate, heart rate, locomotor activity and blood pressure in rats treated chronically with methadone. Over 4 days of treatment, respiratory rate decreased, but partial tolerance appeared to develop during active (night) periods. Decreased heart rate was observed during the night periods and tolerance appeared to develop to this effect. Activity and blood pressure did not change with treatment. The effects of naloxone hydrochloride and naloxone methiodide administration on the methadone-treated rats were also examined and both antagonists increased respiratory rate and heart rate, with only naloxone hydrochloride producing significant increases in activity. Radiotelemetry offers a means of evaluating drug effects on respiratory rate continually in ambulatory, unstressed animals.; http://www.elsevier.com/wps/find/journaldescription.cws_home/506087/description#description; Tanya Lewanowitsch, Jason M. White and Rodney J. Irvine; Copyright © 2003 Elsevier B.V. All rights reserved.

Reversal of morphine, methadone and heroin induced effects in mice by naloxone methiodide

Lewanowitsch, T.; Miller, J.; Irvine, R.
Fonte: Pergamon-Elsevier Science Ltd Publicador: Pergamon-Elsevier Science Ltd
Tipo: Artigo de Revista Científica
Publicado em //2006 EN
Relevância na Pesquisa
46.22%
Opioid overdose, which is commonly associated with opioid induced respiratory depression, is a problem with both therapeutic and illicit opioid use. While the central mechanisms involved in the effects of opioids are well described, it has also been suggested that a peripheral component may contribute to the effects observed. This study aimed to further characterise the effects of the peripherally acting naloxone methiodide on the respiratory, analgesic and withdrawal effects produced by various opioid agonists. A comparison of the respiratory and analgesic effects of morphine, methadone and heroin in male Swiss–Albino mice was conducted and respiratory depressive ED80 doses of each opioid determined. These doses (morphine 9 mg/kg i.p., methadone 7 mg/kg i.p., and heroin 17 mg/kg i.p.) were then used to show that both naloxone (3 mg/kg i.p.) and naloxone methiodide (30–100 mg/kg i.p.) could reverse the respiratory and analgesic effects of these opioid agonists, but only naloxone precipitated withdrawal. Further investigation in female C57BL/6J mice using barometric plethysmography found that both opioid antagonists could reverse methadone induced decreases in respiratory rate and increases in tidal volume. Its effects do not appear to be strain or sex dependent. It was concluded that naloxone methiodide can reverse the respiratory and analgesic actions of a variety of opioid agonists...

The effect of the peripherally acting opioid receptor antgonist, naloxone methiodide, on opioid induced respiratory depression.

Lewanowitsch, Tanya
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado Formato: 285827 bytes; 426671 bytes; 751408 bytes; 524700 bytes; application/pdf; application/pdf; application/pdf; application/pdf
Publicado em //2004 EN
Relevância na Pesquisa
46.32%
Fatal and non-fatal opioid overdoses resulting from opioid induced respiratory depression are a significant problem throughout the world. Whilst the opioid receptor antagonist, naloxone hydrochloride, can effectively reverse opioid overdoses, its use is limited because of the adverse effects it produces. These include severe withdrawal and the reversal of analgesia produced by opioid receptor agonists. In this project, the peripherally acting opioid receptor antagonist, naloxone methiodide, was investigated for its potential to reverse opioid induced respiratory depression without altering centrally mediated effects, such as withdrawal. In the publications presented in this thesis, naloxone hydrochloride and naloxone methiodide were shown to effectively reverse the decreases in respiratory rate produced by the administration of morphine, methadone and heroin in mice. Naloxone hydrochloride and naloxone methiodide also reversed the analgesia produced by these opioid receptor agonist treatments, but only naloxone hydrochloride induced significant withdrawal. The doses of naloxone methiodide required to produce the effects described above were higher than the naloxone hydrochloride doses required. Radioligand binding techniques indicated that this was due to a difference in the affinity of naloxone hydrochloride and naloxone methiodide for µ...

Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia

Hutchinson, M.; Northcutt, A.; Chao, L.; Kearney, J.; Zhang, Y.; Berkelhammer, D.; Loram, L.; Rozeske, R.; Bland, S.; Gleeson, T.; Watkins, L.; Maier, S.
Fonte: Academic Press Inc Publicador: Academic Press Inc
Tipo: Artigo de Revista Científica
Publicado em //2008 EN
Relevância na Pesquisa
56.3%
Recent data suggest that opioids can activate immune-like cells of the central nervous system (glia). This opioid-induced glial activation is associated with decreased analgesia, owing to the release of proinflammatory mediators. Here, we examine in rats whether the putative microglial inhibitor, minocycline, may affect morphine-induced respiratory depression and/or morphine-induced reward (conditioned place preference). Systemic co-administration of minocycline significantly attenuated morphine-induced reductions in tidal volume, minute volume, inspiratory force, and expiratory force, but did not affect morphine-induced reductions in respiratory rate. Minocycline attenuation of respiratory depression was also paralleled with significant attenuation by minocycline of morphine-induced reductions in blood oxygen saturation. Minocycline also attenuated morphine conditioned place preference. Minocycline did not simply reduce all actions of morphine, as morphine analgesia was significantly potentiated by minocycline co-administration. Lastly, morphine dose-dependently increased cyclooxygenase-1 gene expression in a rat microglial cell line, an effect that was dose-dependently blocked by minocycline. Together, these data support that morphine can directly activate microglia in a minocycline-suppressible manner and suggest a pivotal role for minocycline-sensitive processes in the mechanisms of morphine-induced respiration depression...

Glial TLR4 signaling does not contribute to opioid-induced depression of respiration

Zwicker, J.D.; Zhang, Y.; Ren, J.; Hutchinson, M.R.; Rice, K.C.; Watkins, L.R.; Greer, J.J.; Funk, G.D.
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
Publicado em //2014 EN
Relevância na Pesquisa
56.43%
Opioids activate glia in the central nervous system in part by activating the toll-like receptor 4 (TLR4)/myeloid differentiation 2 (MD2) complex. TLR4/MD2-mediated activation of glia by opioids compromises their analgesic actions. Glial activation is also hypothesized as pivotal in opioid-mediated reward and tolerance and as a contributor to opioid-mediated respiratory depression. We tested the contribution of TLR4 to opioid-induced respiratory depression using rhythmically active medullary slices that contain the pre-Bötzinger Complex (preBötC, an important site of respiratory rhythm generation) and adult rats in vivo. Injection with DAMGO (μ-opioid receptor agonist; 50 μM) or bath application of DAMGO (500 nM) or fentanyl (1 μM) slowed frequency recorded from XII nerves to 40%, 40%, or 50% of control, respectively. This DAMGO-mediated frequency inhibition was unaffected by preapplication of lipopolysaccharides from Rhodobacter sphaeroides (a TLR4 antagonist, 2,000 ng/ml) or (+)naloxone (1-10 μM, a TLR4-antagonist). Bath application of (-)naloxone (500 nM; a TLR4 and μ-opioid antagonist), however, rapidly reversed the opioid-mediated frequency decrease. We also compared the opioid-induced respiratory depression in slices in vitro in the absence and presence of bath-applied minocycline (an inhibitor of microglial activation) and in slices prepared from mice injected (ip) 18 h earlier with minocycline or saline. Minocycline had no effect on respiratory depression in vitro. Finally...

Opioids, ventilation and acute pain management

Macintyre, P.; Loadsman, J.; Scott, D.
Fonte: Australian Soc Anaesthetists Publicador: Australian Soc Anaesthetists
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
Relevância na Pesquisa
46.22%
Despite the increasing use of a variety of different analgesic strategies, opioids continue as the mainstay for management of moderate to severe acute pain. However, concerns remain about their potential adverse effects on ventilation. The most commonly used term, respiratory depression, only describes part of that risk. Opioid-induced ventilatory impairment (OIVI) is a more complete term encompassing opioid-induced central respiratory depression (decreased respiratory drive), decreased level of consciousness (sedation) and upper airway obstruction, all of which, alone or in combination, may result in decreased alveolar ventilation and increased arterial carbon dioxide levels. Concerns about OIVI are warranted, as deaths related to opioid administration in the acute pain setting continue to be reported. Risks are often said to be higher in patients with obstructive sleep apnoea. However; the tendency to use the term 'obstructive sleep apnoea' to encompass the much broader spectrum of sleep- and obesity-related hypoventilation syndromes and the related misuse of terminology in papers relating to obstructive sleep apnoea and sleep-disordered breathing remain significant problems in discussions of opioid-related effects. Opioids given for management of acute pain must be titrated to effect for each patient. However...