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

2014 ◽  
Vol 117 (8) ◽  
pp. 857-868 ◽  
Author(s):  
Jennifer D. Zwicker ◽  
Yong Zhang ◽  
Jun Ren ◽  
Mark R. Hutchinson ◽  
Kenner C. Rice ◽  
...  
Keyword(s):  
Respiratory Depression ◽  
Respiratory Rhythm ◽  
Opioid Antagonist ◽  
Adult Rats ◽  
Opioid Receptor Agonist ◽  
Bath Application ◽  
The Central Nervous System ◽  
Tlr4 Antagonist

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, the respiratory depression evoked in anesthetized rats by tail vein infusion of fentanyl was unaffected by subsequent injection of (+)naloxone, but completely reversed by (−)naloxone. These data indicate that neither activation of microglia in preBötC nor TLR4/MD2-activation contribute to opioid-induced respiratory depression.

scholarly journals Intranasal Borna Disease Virus (BoDV-1) Infection: Insights into Initial Steps and Potential Contagiosity

2019 ◽  
Vol 20 (6) ◽  
pp. 1318 ◽  
Author(s):  
Alexandra Kupke ◽  
Sabrina Becker ◽  
Konstantin Wewetzer ◽  
Barbara Ahlemeyer ◽  
Markus Eickmann ◽  
...  
Keyword(s):  
Viral Infections ◽  
Cell Types ◽  
Nerve Fibers ◽  
Olfactory Pathway ◽  
Adult Rats ◽  
The Central Nervous System ◽  
Receptor Neurons

Mammalian Bornavirus (BoDV-1) typically causes a fatal neurologic disorder in horses and sheep, and was recently shown to cause fatal encephalitis in humans with and without transplant reception. It has been suggested that BoDV-1 enters the central nervous system (CNS) via the olfactory pathway. However, (I) susceptible cell types that replicate the virus for successful spread, and (II) the role of olfactory ensheathing cells (OECs), remained unclear. To address this, we studied the intranasal infection of adult rats with BoDV-1 in vivo and in vitro, using olfactory mucosal (OM) cell cultures and the cultures of purified OECs. Strikingly, in vitro and in vivo, viral antigen and mRNA were present from four days post infection (dpi) onwards in the olfactory receptor neurons (ORNs), but also in all other cell types of the OM, and constantly in the OECs. In contrast, in vivo, BoDV-1 genomic RNA was only detectable in adult and juvenile ORNs, nerve fibers, and in OECs from 7 dpi on. In vitro, the rate of infection of OECs was significantly higher than that of the OM cells, pointing to a crucial role of OECs for infection via the olfactory pathway. Thus, this study provides important insights into the transmission of neurotropic viral infections with a zoonotic potential.

scholarly journals Coadministration of the AMPAKINE CX717 with Propofol Reduces Respiratory Depression and Fatal Apneas

2013 ◽  
Vol 118 (6) ◽  
pp. 1437-1445 ◽  
Author(s):  
Jun Ren ◽  
Floriane Lenal ◽  
Michael Yang ◽  
Xiuqing Ding ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Safety Margin ◽  
Adult Rats ◽  
Control Frequency ◽  
Rat Brainstem ◽  
Nerve Recordings ◽  
Working Heart

Abstract Background: Propofol (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol’s disadvantages include the induction of respiratory depression and apnea. Here, the authors report a clinically feasible pharmacological solution for reducing propofol-induced respiratory depression via a mechanism that does not interfere with anesthesia. Specifically, they test the hypothesis that the AMPAKINE CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from propofol-induced severe apnea. Methods: The actions of propofol and the AMPAKINE CX717 were measured via (1) ventral root recordings from newborn rat brainstem–spinal cord preparations, (2) phrenic nerve recordings from an adult mouse in situ working heart–brainstem preparation, and (3) plethysmographic recordings from unrestrained newborn and adult rats. Results: In vitro, respiratory depression caused by propofol (2 μm, n = 11, mean ± SEM, 41±5% of control frequency, 63±5% of control duration) was alleviated by CX717 (n = 4, 50–150 μm). In situ, a decrease in respiratory frequency (44±9% of control), phrenic burst duration (66±7% of control), and amplitude (78±5% of control) caused by propofol (2 μm, n = 5) was alleviated by coadministration of CX717 (50 μm, n = 5). In vivo, pre- or coadministration of CX717 (20–25mg/kg) with propofol markedly reduced propofol-induced respiratory depression (n = 7; 20mg/kg) and propofol-induced lethal apnea (n = 6; 30mg/kg). Conclusions: Administration of CX717 before or in conjunction with propofol provides an increased safety margin against profound apnea and death.

Sulfated cholecystokinin octapeptide in the rat: pontomedullary distribution and modulation of the respiratory pattern

1999 ◽  
Vol 77 (7) ◽  
pp. 490-504 ◽  
Author(s):  
Howard H Ellenberger ◽  
Frank M Smith
Keyword(s):  
Respiratory Rhythm ◽  
Mean Amplitude ◽  
Neonatal Rat ◽  
Respiratory Pattern ◽  
Reticular Nucleus ◽  
Adult Rats ◽  
Cholecystokinin Octapeptide ◽  
Ventral Respiratory Group

We performed anatomical and physiological studies to determine the site and actions of sulfated cholecystokinin octapeptide (CCK8-S) on breathing. Peptide locations were determined by combined immunodetection of CCK8-S- containing synaptic varicosities and retrograde labeling of medullary neurons projecting to the ventral respiratory group. Retrogradely labeled neurons and CCK8-S immunolabeled varicosities overlapped within the nuclei of the solitary tract, ventral respiratory group, and the Kölliker-Fuse nucleus. Additional CCK8-S immunoreactive terminals were located in the rostroventrolateral medullary reticular nucleus, lateral paragigantocellular reticular nucleus, and the caudal pontine reticular nucleus. The respiratory effects of CCK8-S, which binds to CCKA and CCKB receptors, were examined by intravenous injection in adult rats and by bath application in the in vitro neonatal rat brainstem - spinal cord preparation. CCK8-S produced an increase in the mean amplitude of diaphragmatic electromyogram (EMG) of 28 ± 35% (SD) and a decrease in mean respiratory interval of 13 ± 4% in vivo. In vitro, CCK8-S significantly increased inspiratory duration and decreased respiratory interval, primarily by shortening expiratory duration. CCK8-unsulfated, a specific agonist for CCKB receptors, did not produce these effects. CCK8-S effects in the in vitro preparation were partially blocked by the CCK receptor antagonist lorglumide (final bath concentration 600 nM). These results suggest that CCK8-S modulates the respiratory rhythm via CCKA receptors within one or more medullary or pontine respiratory groups in both neonatal and adult rats.Key words: neuropeptide, ventral respiratory group, medulla, pons, respiratory network.

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

2012 ◽  
Vol 113 (7) ◽  
pp. 1004-1011 ◽  
Author(s):  
Jun Ren ◽  
Xiuqing Ding ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Circulatory Support ◽  
Respiratory Drive ◽  
Drug Induced ◽  
Adult Rats ◽  
Respiratory Rhythmogenesis ◽  
Life Threatening ◽  
Preclinical And Clinical Studies

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, whereas CX717 did not. These data demonstrated that ethanol and pentobarbital together caused severe respiratory depression, including lethal apnea, via synergistic actions that blunt chemoreceptive responses to hypoxia and hypercapnia and suppress central respiratory rhythmogenesis. The ampakine CX717 markedly reduced the severity of respiratory depression.

scholarly journals Opioid-induced Respiratory Depression Is Only Partially Mediated by the preBötzinger Complex in Young and Adult Rabbits In Vivo

2015 ◽  
Vol 122 (6) ◽  
pp. 1288-1298 ◽  
Author(s):  
Astrid G. Stucke ◽  
Justin R. Miller ◽  
Ivana Prkic ◽  
Edward J. Zuperku ◽  
Francis A. Hopp ◽  
...  
Keyword(s):  
Respiratory Rate ◽  
Respiratory Depression ◽  
Respiratory Rhythm ◽  
Respiratory Drive ◽  
Phase Duration ◽  
Homocysteic Acid ◽  
Opioid Receptor Agonist ◽  
Prebotzinger Complex ◽  
Prebötzinger Complex

Abstract Background: The preBötzinger Complex (preBC) plays an important role in respiratory rhythm generation. This study was designed to determine whether the preBC mediated opioid-induced respiratory rate depression at clinically relevant opioid concentrations in vivo and whether this role was age dependent. Methods: Studies were performed in 22 young and 32 adult New Zealand White rabbits. Animals were anesthetized, mechanically ventilated, and decerebrated. The preBC was identified by the tachypneic response to injection of d,l-homocysteic acid. (1) The μ-opioid receptor agonist [d-Ala2,N-Me-Phe4,Gly-ol]-enkephalin (DAMGO, 100 μM) was microinjected into the bilateral preBC and reversed with naloxone (1 mM) injection into the preBC. (2) Respiratory depression was achieved with intravenous remifentanil (0.08 to 0.5 μg kg−1 min−1). Naloxone (1 mM) was microinjected into the preBC in an attempt to reverse the respiratory depression. Results: (1) DAMGO injection depressed respiratory rate by 6 ± 8 breaths/min in young and adult rabbits (mean ± SD, P < 0.001). DAMGO shortened the inspiratory and lengthened the expiratory fraction of the respiratory cycle by 0.24 ± 0.2 in adult and young animals (P < 0.001). (2) During intravenous remifentanil infusion, local injection of naloxone into the preBC partially reversed the decrease in inspiratory fraction/increase in expiratory fraction in young and adult animals (0.14 ± 0.14, P < 0.001), but not the depression of respiratory rate (P = 0.19). PreBC injections did not affect respiratory drive. In adult rabbits, the contribution of non-preBC inputs to expiratory phase duration was larger than preBC inputs (3.5 [−5.2 to 1.1], median [25 to 75%], P = 0.04). Conclusions: Systemic opioid effects on respiratory phase timing can be partially reversed in the preBC without reversing the depression of respiratory rate.

scholarly journals Activating α4β2 Nicotinic Acetylcholine Receptors Alleviates Fentanyl-induced Respiratory Depression in Rats

2019 ◽  
Vol 130 (6) ◽  
pp. 1017-1031 ◽  
Author(s):  
Jun Ren ◽  
Xiuqing Ding ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Nicotinic Acetylcholine Receptors ◽  
Nicotinic Receptor ◽  
Acetylcholine Receptors ◽  
Receptor Agonist ◽  
Respiratory Rhythm ◽  
Pharmacologic Therapy ◽  
Nicotinic Acetylcholine

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Opioid analgesics are widely used for treatment of acute, postoperative, and chronic pain. However, activation of opioid receptors can result in severe respiratory depression. There is an unmet clinical need to develop a pharmacologic therapy to counter opioid-induced respiratory depression without interfering with analgesia. Further, additional advances to confront accidental lethal overdose with the use of fentanyl and other opioids are needed. Here, the authors test the hypothesis that activation of nicotinic receptors expressed within respiratory rhythm–generating networks would counter opioid-induced respiratory depression without compromising analgesia. Methods Respiratory neural discharge was measured using in vitro brainstem–spinal cord and medullary slice rat preparations. In vivo, plethysmographic recording, nociception testing, and righting reflexes were used to examine respiratory ventilation, analgesia, and sedation, respectively. Results The administration of nicotine, selective α4β2 nicotinic receptor agonist A85380, but not α7 nicotinic receptor agonist PNU282987, reversed opioid-induced respiratory depression in neonatal pups in vitro and in vivo. In adult rats in vivo, administration of A85380 (0.03 mg/kg), but not PNU282987, provides a rapid and robust reversal of fentanyl-induced decrease in respiratory rate (93.4 ± 33.7% of control 3 min after A85380 vs. 31 ± 20.5% of control after vehicle, n = 8 each, P < 0.001), without marked side effects. The coadministration of A85380 (0.06 mg/kg) with fentanyl or remifentanil markedly reduced respiratory depression and apneas, and enhanced the fentanyl-induced analgesia, as evidenced by increased paw withdrawal latency in Hargreaves plantar test (14.4 ± 2.8 s vs. vehicle: 11.3 ± 2.4 s, n = 8 each, P = 0.013) and decreased formalin-induced nocifensive duration (2.5 ± 2.4 min vs. vehicle: 5.4 ± 2.7 min, n = 8 each, P = 0.029). Conclusions The novel strategy of targeting α4β2 nicotinic acetylcholine receptors has the potential for advancing pain control and reducing opioid-induced respiratory depression and overdose.

Sulfide-induced perturbations of the neuronal mechanisms controlling breathing in rats

1995 ◽  
Vol 78 (2) ◽  
pp. 433-440 ◽  
Author(s):  
J. J. Greer ◽  
R. J. Reiffenstein ◽  
A. F. Almeida ◽  
J. E. Carter
Keyword(s):  
Respiratory Rhythm ◽  
Intraperitoneal Administration ◽  
Experimental Models ◽  
Neonatal Rat ◽  
Ventrolateral Medulla ◽  
Neonatal Rats ◽  
Breathing Patterns ◽  
Adult Rats

The effects of sulfide on neonatal rat respiration were studied. Two in vitro experimental models were utilized: the isolated brain stem-spinal cord preparation and the medullary slice preparation containing respiratory rhythm-generating regions from neonatal rats. Plethysmographic measurements of the effects of sulfide on the breathing patterns of unanesthetized neonatal rats were also made to compare the sensitivities of neonatal and adult rats to sulfide toxicity. In vitro, sulfide acted at sites within the ventrolateral medulla to depress the frequency of respiratory rhythmic discharge by approximately 50–60%. However, the neuronal network underlying respiratory rhythmogenesis continued to function in the presence of concentrations of sulfide far beyond those deemed to be lethal in vivo. Intraperitoneal administration of sulfide caused a dose-dependent decrease in the frequency and amplitude of breathing of neonatal rats of all ages (0–19 days postnatal), although the sensitivity to sulfide increased with age. We hypothesize that the rapid suppression of breathing caused by sulfide is due to changes in neuronal excitability within respiratory rhythm-generating centers rather than, as previously hypothesized, to perturbations of cellular oxidative metabolism.

Thiamine transport in the central nervous system

1976 ◽  
Vol 230 (4) ◽  
pp. 1101-1107 ◽  
Author(s):  
R Spector
Keyword(s):  
Choroid Plexus ◽  
Intraventricular Injection ◽  
Simple Diffusion ◽  
Thiamine Transport ◽  
Choroid Plexuses ◽  
The Central Nervous System ◽  
The Brain ◽  
Thiamine Phosphates

Total thiamine (free thiamine and thiamine phosphates) transport into the cerebrospinal fluid (CSF), brain, and choroid plexus and out of the CSF was measured in rabbits. In vivo, total thiamine transport into CSF, choroid plexus, and brain was saturable. At the normal plasma total thiamine concentration, less than 5% of total thiamine entry into CSF, choroid plexus, and brain was by simple diffusion. The relative turnovers of total thiamine in choroid plexus, whole brain, and CSF were 5, 2, and 14% per h, respectively, when measured by the penetration of 35S-labeled thiamine injected into blood. From the CSF, clearance of [35S]thiamine relative to mannitol was not saturable after the intraventricular injection of various concentrations of thiamine. However, a portion of the [35S]thiamine cleared from the CSF entered brain by a saturable mechanism. In vitro, choroid plexuses, isolated from rabbits and incubated in artificial CSF, accumulated [35S]thiamine against a concentration gradient by an active saturable process that did not depend on pyrophosphorylation of the [35S]thiamine. The [35S]thiamine accumulated within the choroid plexus in vitro was readily released. These results were interpreted as showing that the entry of total thiamine into the brain and CSF from blood is regulated by a saturable transport system, and that the locus of this system may be, in part, in the choroid plexus.

scholarly journals In Vivo and In Vitro Toxicodynamic Analyses of New Quinolone-and Nonsteroidal Anti-Inflammatory Drug-Induced Effects on the Central Nervous System

1999 ◽  
Vol 43 (5) ◽  
pp. 1091-1097 ◽  
Author(s):  
Hideki Kita ◽  
Hirotami Matsuo ◽  
Hitomi Takanaga ◽  
Junichi Kawakami ◽  
Koujirou Yamamoto ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Threshold Concentration ◽  
Current Response ◽  
Drug Induced ◽  
Inhibition Ratio ◽  
New Quinolones ◽  
The Central Nervous System ◽  
Anti Inflammatory

ABSTRACT We investigated the correlation between an in vivo isobologram based on the concentrations of new quinolones (NQs) in brain tissue and the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for the occurrence of convulsions in mice and an in vitro isobologram based on the concentrations of both drugs for changes in the γ-aminobutyric acid (GABA)-induced current response in Xenopus oocytes injected with mRNA from mouse brains in the presence of NQs and/or NSAIDs. After the administration of enoxacin (ENX) in the presence or absence of felbinac (FLB), ketoprofen (KTP), or flurbiprofen (FRP), a synergistic effect was observed in the isobologram based on the threshold concentration in brain tissue between mice with convulsions and those without convulsions. The three NSAIDs did not affect the pharmacokinetic behavior of ENX in the brain. However, the ENX-induced inhibition of the GABA response in the GABAA receptor expressed in Xenopus oocytes was enhanced in the presence of the three NSAIDs. The inhibition ratio profiles of the GABA responses for both drugs were analyzed with a newly developed toxicodynamic model. The inhibitory profiles for ENX in the presence of NSAIDs followed the order KTP (1.2 μM) > FRP (0.3 μM) > FLB (0.2 μM). These were 50- to 280-fold smaller than those observed in the absence of NSAIDs. The inhibition ratio (0.01 to 0.02) of the GABAA receptor in the presence of both drugs was well-fitted to the isobologram based on threshold concentrations of both drugs in brain tissue between mice with convulsions and those without convulsions, despite the presence of NSAIDs. In mice with convulsions, the inhibitory profiles of the threshold concentrations of both drugs in brain tissue of mice with convulsions and those without convulsions can be predicted quantitatively by using in vitro GABA response data and toxicodynamic model.

scholarly journals In vitro analysis of the origin and maintenance of O-2Aadult progenitor cells.

1992 ◽  
Vol 116 (1) ◽  
pp. 167-176 ◽  
Author(s):  
D Wren ◽  
G Wolswijk ◽  
M Noble
Keyword(s):  
Adult Life ◽  
Cell Types ◽  
Adult Rats ◽  
Optic Nerves ◽  
Limited Life ◽  
Old Rats ◽  
Vitro Analysis

We have been studying the differing characteristics of oligodendrocyte-type-2 astrocyte (O-2A) progenitors isolated from optic nerves of perinatal and adult rats. These two cell types display striking differences in their in vitro phenotypes. In addition, the O-2Aperinatal progenitor population appears to have a limited life-span in vivo, while O-2Aadult progenitors appear to be maintained throughout life. O-2Aperinatal progenitors seem to have largely disappeared from the optic nerve by 1 mo after birth, and are not detectable in cultures derived from optic nerves of adult rats. In contrast, O-2Aadult progenitors can first be isolated from optic nerves of 7-d-old rats and are still present in optic nerves of 1-yr-old rats. These observations raise two questions: (a) From what source do O-2Aadult progenitors originate; and (b) how is the O-2Aadult progenitor population maintained in the nerve throughout life? We now provide in vitro evidence indicating that O-2Aadult progenitors are derived directly from a subpopulation of O-2Aperinatal progenitors. We also provide evidence indicating that O-2Aadult progenitors are capable of prolonged self renewal in vitro. In addition, our data suggests that the in vitro generation of oligodendrocytes from O-2Aadult progenitors occurs primarily through asymmetric division and differentiation, in contrast with the self-extinguishing pattern of symmetric division and differentiation displayed by O-2Aperinatal progenitors in vitro. We suggest that O-2Aadult progenitors express at least some properties of stem cells and thus may be able to support the generation of both differentiated progeny cells as well as their own continued replenishment throughout adult life.

Sign in / Sign up

Export Citation Format

Share Document