Opioid Action on Respiratory Neuron Activity of the Isolated Respiratory Network in Newborn Rats

Background: Underlying mechanisms behind opioid-induced respiratory depression are not fully understood. The authors investigated changes in burst rate, intraburst firing frequency, membrane properties, as well as presynaptic and postsynaptic events of respiratory neurons in the isolated brainstem after administration of opioid receptor agonists.

Methods: Newborn rat brainstem-spinal cord preparations were used and superfused with [mu]-, [kappa]-, and [delta]-opioid receptor agonists. Whole cell recordings were performed from three major classes of respiratory neurons (inspiratory, preinspiratory, and expiratory).

Results: Mu- and [kappa]-opioid receptor agonists reduced the spontaneous burst activity of inspiratory neurons and the C4 nerve activity. Forty-two percent of the inspiratory neurons were hyperpolarized and decreased in membrane resistance during opioid-induced respiratory depression. Furthermore, under synaptic block by tetrodotoxin perfusion, similar changes of inspiratory neuronal membrane properties occurred after application of [mu]- and [kappa]-opioid receptor agonists. In contrast, resting membrane potential and membrane resistance of preinspiratory and majority of expiratory neurons were unchanged by opioid receptor agonists, even during tetrodotoxin perfusion. Simultaneous recordings of inspiratory and preinspiratory neuronal activities confirmed the selective inhibition of inspiratory neurons caused by [mu]- and [kappa]-opioid receptor agonists. Application of opioids reduced the slope of rising of excitatory postsynaptic potentials evoked by contralateral medulla stimulation, resulting in a prolongation of the latency of successive first action potential responses.     

Nitric Oxide Involvement in Hypoxic Dilation of Pial Arteries in the Cat

Background: The reactivity of cerebral arteries to different stimuli varies according to vessel size. Whether nitric oxide mediates hypoxic vasodilation is controversial The authors considered this question by measuring the diameter of pial arteries and arterioles with or without exposure to the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME).

Methods: The cranial window technique, combined with microscopic video recording, was used in an experiment involving 20 cats anesthetized with fentanyl and midazolam. The diameters of pial arteries and arterioles were measured under the following conditions: (1) normoxia (PaO2 > 100 mmHg); (2) hypoxia (PaO2 < 45 mmHg); (3) normoxia with L-NAME infusion; and (4) hypoxia with L-NAME infusion. Changes in vessel diameter were analyzed with respect to artery size.

Results: Under hypoxic conditions, arteries and arterioles smaller than 200 micro meter were dilated significantly (P < 0.05). In arterioles smaller than 200 micro meter, L-NAME attenuated this hypoxic vasodilation (P < 0.05). In contrast, under normoxic conditions, L-NAME caused significant vasoconstriction in arteries larger than 100 micro meter but not in arteries smaller than 100 micro meter.     

Naloxone Reversal of Buprenorphine-induced Respiratory Depression

Background: The objective of this investigation was to examine the ability of the opioid antagonist naloxone to reverse respiratory depression produced by the [mu]-opioid analgesic, buprenorphine, in healthy volunteers. The studies were designed in light of the claims that buprenorphine is relatively resistant to the effects of naloxone.

Methods: In a first attempt, the effect of an intravenous bolus dose of 0.8 mg naloxone was assessed on 0.2 mg buprenorphine-induced respiratory depression. Next, the effect of increasing naloxone doses (0.5-7 mg, given over 30 min) on 0.2 mg buprenorphine-induced respiratory depression was tested. Subsequently, continuous naloxone infusions were applied to reverse respiratory depression from 0.2 and 0.4 mg buprenorphine. All doses are per 70 kg. Respiration was measured against a background of constant increased end-tidal carbon dioxide concentration.

Results: An intravenous naloxone dose of 0.8 mg had no effect on respiratory depression from buprenorphine. Increasing doses of naloxone given over 30 min produced full reversal of buprenorphine effect in the dose range of 2-4 mg naloxone. Further increasing the naloxone dose (doses of 5 mg or greater) caused a decline in reversal activity. Naloxone bolus doses of 2-3 mg, followed by a continuous infusion of 4 mg/h, caused full reversal within 40-60 min of both 0.2 and 0.4 mg buprenorphine-induced respiratory depression.     

Involvement of Peripheral Adenosine A2 Receptors in Adenosine A1 Receptor-Mediated Recovery of Respiratory Motor Function After Upper Cervical Spinal Cord Hemisection

Abstract

Background/Objective: In an animal model of spinal cord injury, a latent respiratory motor pathway can be pharmacologically activated through central adenosine A₁ receptor antagonism to restore respiratory function after cervical (C2) spinal cord hemisection that paralyzes the hemidiaphragm ipsilateral to injury. Although respiration is modulated by central and peripheral mechanisms, putative involvement of peripheral adenosine A₂ receptors in functional recovery in our model is untested. The objective of this study was to assess the effects of peripherally located adenosine A₂ receptors on recovery of respiratory function after cervical (C2) spinal cord hemisection.

Methods: Respiratory activity was electrophysiologically assessed (under standardized recording conditions) in C2-hemisected adult rats with the carotid bodies intact (H-CBI; n = 12) or excised (H-CBE; n = 12). Animals were administered the adenosine A2 receptor agonist, CGS-21680, followed by the A1 receptor antagonist, 1, 3-dipropyl-8-cyclopentylxanthine (DPCPX), or administered DPCPX alone. Recovered respiratory activity, characterized as drug-induced activity in the previously quiescent left phrenic nerve of C2-hemisected animals in H-CBI and H-CBE rats, was compared. Recovered respiratory activity was calculated by dividing drug-induced activity in the left phrenic nerve by activity in the right phrenic nerve.

Results: Administration of CGS-21680 before DPCPX (n = 6) in H-CBI rats induced a significantly greater recovery (58.5 ± 3.6%) than when DPCPX (42.6 ± 4.6%) was administered (n = 6) alone. In H-CBE rats, prior administration of CGS-21680 (n = 6) did not enhance recovery over that induced by DPCPX (n = 6) alone. Recovery in H-CBE rats amounted to 39.7 ± 3.7% and 38.4 + 4.2%, respectively.

Conclusions: Our results suggest that adenosine A2 receptors located in the carotid bodies can enhance the magnitude of adenosine A1 receptor-mediated recovery of respiratory function after C2 hemisection. We conclude that a novel approach of targeting peripheral and central adenosine receptors can be therapeutically beneficial in alleviating compromised respiratory function after cervical spinal cord injury.     

Recurrence of Respiratory Depression Following Neurolept Analgesia

Fentanyl, though generally regarded as a short-acting narcotic analgesic, can give unexpected respiratory depression several hours after the last dose. This potentially very dangerous effect is explained in pharmacokinetic studies by a mobilisation of fentanyl from tissue stores. In this report we describe a patient who, following a Harrington correction for scoliosis done with neurolept analgesia, developed a severe respiratory depression 5 h after the last dose of fentanyl.     

Involvement of Glutamate Receptors in Strychnine- and Bicuculline-induced Allodynia in Conscious Mice

Background: Glycine and gamma-aminobutyric acid (GABA) are inhibitory neurotransmitters that appear to be important in sensory processing in the spinal dorsal horn. Intrathecal administration of strychnine (strychnine-sensitive glycine receptor antagonist) or bicuculline (GABAA antagonist) was reported to induce allodynia. Although the strychnine-induced allodynia was shown to be mediated through the N-methyl-D-aspartate (NMDA)-type glutamate receptor, it is not clear whether the bicuculline-evoked allodynia is mediated through the glutamate receptor system or how different the allodynia induced by strychnine and bicuculline are.

Methods: Male ddY mice weighing 20+/-2 g were used in this study. A 27-G stainless-steel needle attached to a microsyringe was inserted between the L5 and L6 vertebrae by a slight modification of the method of Hylden and Wilcox. Drugs in vehicle were injected slowly into the subarachnoid space to conscious mice at 22+/-2 degrees Celsius. The volume of the intrathecal injection was 5 micro liter. Studies on allodynia were carried out essentially according to the method of Yaksh and Harty.

Results: The intrathecal administration of strychnine or bicuculline in conscious mice resulted in allodynia elicited by nonnoxious brushing of the flanks. The maximum allodynia induced by strychnine was observed 5 min after intrathecal injection, but that induced by bicuculline was observed 10 min after intrathecal injection. Both responses gradually decreased over the experimental period of 50 min. The allodynia induced by strychnine was dose-dependently relieved by NMDA receptor antagonists (D-AP5, ketamine, and 7-Cl-KYNA) and non-NMDA receptor antagonists (GAMS and CNQX) but not by metabotropic receptor antagonists (L-AP3 and L-AP4). On the other hand, allodynia induced by bicuculline was dose-dependently relieved by GAMS, L-AP3, and L-AP4, but not by D-AP5, ketamine, 7-Cl-KYNA, and CNQX. Whereas the strychnine-evoked allodynia was dose-dependently relieved by the nitric oxide synthase inhibitor Nomega -nitro-L-arginine methyl ester (L-NAME) and the soluble guanylate cyclase inhibitor methylene blue, the bicuculline-induced one was dose-dependently relieved by methylene blue but not by L-NAME.     

Speed of Onset and Offset and Mechanisms of Ventilatory Depression from Sevoflurane: An Experimental Study in the Cat

Background: Inhalation anesthetics depress breathing dose dependently. The authors studied the dynamics of ventilation on changes in end-tidal sevoflurane partial pressure. To learn more about the mechanisms of sevoflurane-induced respiratory depression, the authors also studied its influence on the dynamic ventilatory response to carbon dioxide.

Methods: Experiments were performed in cats anesthetized with [Greek small letter alpha] chloralose-urethane. For protocol 1, step changes in end-tidal sevoflurane partial pressure were applied and inspired ventilation was measured. Breath-to-breath inspired ventilation was related to the sevoflurane concentration in a hypothetical effect compartment based on an inhibitory sigmoid Emax model. For protocol 2, step changes in the end-tidal partial pressure of carbon dioxide were applied at 0, 0.5, and 1% end-tidal sevoflurane. The inspired ventilation-end-tidal partial pressure of carbon dioxide data were analyzed using a two-compartment model of the respiratory controller, which consisted of a fast peripheral and slow central compartment. Values are the mean +/- SD.

Results: In protocol 1, the effect-site half-life of respiratory changes caused by alterations in end-tidal sevoflurane partial pressure was 3.6 +/- 1.0 min. In protocol 2, at 0.5% sevoflurane, the central and peripheral carbon dioxide sensitivities decreased to 43 +/- 20% and 36 +/- 18% of control. At 1% sevoflurane, the peripheral carbon dioxide sensitivity decreased further, to 12 +/- 13% of control, whereas the central carbon dioxide sensitivity showed no further decrease.     

Respiratory Sites of Action of Propofol: Absence of Depression of Peripheral Chemoreflex Loop by Low-dose Propofol

Background: Propofol has a depressant effect on metabolic ventilatory control, causing depression of the ventilatory response to acute isocapnic hypoxia, a response mediated via the peripheral chemoreflex loop. In this study, the authors examined the effect of sedative concentrations of propofol on the dynamic ventilatory response to carbon dioxide to obtain information about the respiratory sites of action of propofol.

Methods: In 10 healthy volunteers, the end-tidal carbon dioxide concentration was varied according to a multifrequency binary sequence that involved 13 steps into and 13 steps out of hypercapnia (total duration, 1,408 s). In each subject, two control studies, two studies at a plasma target propofol concentration of 0.75 [mu]g/ml (Plow), and two studies at a target propofol concentration of 1.5 [mu]g/ml (Phigh) were performed. The ventilatory responses were separated into a fast peripheral component and a slow central component, characterized by a time constant, carbon dioxide sensitivity, and apneic threshold. Values are mean +/- SD.

Results: Plasma propofol concentrations were approximately 0.5 [mu]g/ml for Plow and approximately 1.3 mg/ml for Phigh. Propofol reduced the central carbon dioxide sensitivity from 1.5 +/- 0.4 to 1.2 +/- 0.3 (Plow;P < 0.01 vs. control) and 0.9 +/- 0.1 l [middle dot] min-1 [middle dot] mmHg-1 (Phigh;P < 0.001 vs. control). The peripheral carbon dioxide sensitivity remained unaffected by propofol (control, 0.5 +/- 0.3; Plow, 0.5 +/- 0.2; Phigh, 0.5 +/- 0.2 l [middle dot] min-1 [middle dot] mmHg-1). The apneic threshold was reduced from 36.3 +/- 2.7 (control) to 35.0 +/- 2.1 (Plow;P < 0.01 vs. control) and to 34.6 +/- 1.9 mmHg (Phigh;P < 0.01 vs. control).     

Morphine Enhances Pharmacological Preconditioning by Isoflurane: Role of Mitochondrial KATP Channels and Opioid Receptors

Background: Adenosine triphosphate-regulated potassium channels mediate protection against myocardial infarction produced by volatile anesthetics and opioids. We tested the hypothesis that morphine enhances the protective effect of isoflurane by activating mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors.

Methods: Barbiturate-anesthetized rats (n = 131) were instrumented for measurement of hemodynamics and subjected to a 30 min coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size was determined using triphenyltetrazolium staining. Rats were randomly assigned to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar concentration [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane (1.0 MAC). Isoflurane was administered for 30 min and discontinued 15 min before coronary occlusion. In eight additional groups of experiments, rats received 5-hydroxydecanoic acid (5-HD; 10 mg/kg) or naloxone (6 mg/kg) in the presence or absence of isoflurane, morphine, and morphine plus isoflurane.

Results: Isoflurane (1.0 MAC) and morphine (0.3 mg/kg) reduced infarct size (41 +/- 3%; n = 13 and 38 +/- 2% of the area at risk; n = 10, respectively) as compared to control experiments (59 +/- 2%; n = 10). Morphine plus isoflurane further decreased infarct size to 26 +/- 3% (n = 11). 5-HD and naloxone alone did not affect infarct size, but abolished cardioprotection produced by isoflurane, morphine, and morphine plus isoflurane.     

硬膜外布比卡因镇痛减轻上腹部手术病人术后肺功能抑制

目的：研究术后硬膜外镇痛对上腹部手术病人呼吸功能的保护作用。方法：３０例硬膜外麻醉下行胆囊切除术病人分为两组：镇痛组１５例，术后保留硬膜外导管４８ｈ，每４～６ｈ注入０．２％布比卡因５ｍｌ镇痛；对照组１５例，用生理盐水代替布比卡因作对照。围手术期监测肺功能、ＳｐＯ２和血气。结果：两组病人术后早期肺功能均明显抑制。但镇痛组的呼吸抑制远比对照组为轻，术后１２ｈ的Ｖｃ、ＩＲＶ、ＥＲＶ、ＦＥＶ１．０、ＦＶＣ、ＭＭＦ和ＰＦＲ分别达术前值的７０．２１％、６２．３８％、６５．９４％、６１．９２％、６４．７４％、５７．５７％和５９．４０％，术后４８～７２ｈ的肺功能恢复至术前水平的７０％～８０％；术后第７天达９０％左右；ＰａＯ２和ＰａＣＯ２变化不大。结论：术后硬膜外注入０．２％布比卡因镇痛能有效地减轻上腹部手术病人术后肺功能抑制。     

Functional μ Opioid Receptors Are Reduced in the Spinal Cord Dorsal Horn of Diabetic Rats

Background: The mechanisms of decreased spinal analgesic potency of morphine in neuropathic pain are not fully known. Agonist-stimulated [35S]GTP[gamma]S receptor autoradiography has been used to measure receptor activation of G proteins in vitro. Using this technique, we determined changes in the functional [mu] opioid receptors in the spinal dorsal horn in diabetic rats.

Methods: Rats were rendered diabetic with an intraperitoneal injection of streptozotocin. The lumbar spinal cord was obtained from age-matched normal and diabetic rats 4 weeks after streptozotocin treatment. [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAMGO, 10 [mu]m)-stimulated [35S]GTP[gamma]S binding was performed in both tissue sections and isolated membranes.

Results: The DAMGO-stimulated [35S]GTP[gamma]S binding in the spinal dorsal horn was significantly reduced (approximately 37%) in diabetic rats compared with normal rats. However, [35S]GTP[gamma]S bindings in the spinal dorsal horn stimulated by other G protein-coupled receptor agonists, including [D-Pen2,D-Pen5]-enkephalin, R (-)N6-(2-phenylisopropyl)-adenosine, and WIN-55212, were not significantly altered in diabetic rats. The basal [35S]GTP[gamma]S binding in the spinal dorsal horn was slightly (approximately 13%) but significantly increased in diabetic rats. Western blot analysis revealed no significant difference in the expression of the [alpha] subunits of Gi and Go proteins in the dorsal spinal cord between normal and diabetic rats.     

Tramadol in the treatment of pain

Tramadol hydrochloride is a centrally-acting, synthetic analgesic with a dual mechanism of action-weak opioid and monoaminergic effects. Tramadol is a racemic mixture and its mechanism of action via opioid and noradrenergic/serotonergic mechanisms is related to the independent effects of its two enantiomers. Interestingly, the enantiomers act synergistically to achieve better antinociceptive effect without enhancing side effects, moreover, lowering respiratory depression and tolerance/dependence. In several post-marketing surveillance studies tramadol is showed as effective as codeine, penthazocine, pethidine and morphine with good tolerability. Tramadol might be analgesic of choice for a wide variety of painful conditions.     

Respiratory Depression after Epidural Morphine in the Postoperative Period. Influence of Posture

Twelve females scheduled for elective lower abdominal surgery received 4 mg of morphine by lumbar epidural injection for postoperative pain relief. The patients were divided into two groups nursed postoperatively in a supine or 45 degree elevated position, respectively. Mouth occlusion pressure during CO2 stimulation was used for the determination of respiratory depression, following epidural morphine. No significant difference in occlusion pressure was found between the two groups. Within the groups a significant reduction of the occlusion pressure was found when compared with the value obtained immediately before the administration of epidural morphine. However, compared with the value obtained the day before surgery, no significant reduction of the occlusion pressure was observed. It is concluded that the 45 degree elevated position does not protect against the occurrence of respiratory depression following epidural morphine.     

Role Central Mu, Delta-1, and Kappa-1 Opioid Receptors in Opioid-induced Muscle Rigidity in the Rat

Background: Opioids appear to produce their physiologic effects by binding to at least three types of opioid receptors, the mu (micro), delta (delta), and kappa (kappa) receptors. Muscle rigidity occurs after administration of supra-analgesic doses of potent micro-preferring agonists like alfentanil. The role of different supraspinal opioid receptors in this rigidity has been addressed only recently. To elucidate the contribution of central micro, delta, and kappa receptors to muscle rigidity, the effects of intracerebroventricularly administered opioid receptor-selective agonists and antagonists on alfentanil-induced muscle rigidity were examined in rats.

Methods: Rats in which chronic intracerebroventricular cannulae had been implanted received an intracerebroventricular infusion of either saline or a micro (D-Ala2,N-Me-Phe4 -Gly5 -ol-enkephalin; DAMGO), delta1 (D-Pen2,D-Pen5 -enkephalin; DPDPE), or kappa1 (trans-(plus/minus)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohex yl)-benzene-acetamide methane sulfonate; U50,488H) opioid agonist. Ten minutes later, they received either saline or the micro-agonist alfentanil subcutaneously. Muscle rigidity was assessed using hindlimb electromyographic activity. Different groups of animals were pretreated with an intracerebroventricular infusion of either saline or a micro (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2; CTAP), delta (naltrindole), or kappa1 (norbinaltorphimine) opioid antagonist before administration of either saline or a selective intracerebroventricular agonist.

Results: The micro agonist DAMGO alone dose-dependently induced muscle rigidity. This effect was antagonized by pretreatment with the micro-selective antagonist CTAP. Neither DPDPE nor U50,488H, when administered alone, affected muscle tone. However, both the delta1 and kappa1 agonists dose-dependently attenuated alfentanil-induced rigidity. This antagonism of alfentanil rigidity was abolished after pretreatment with the delta (naltrindole) and kappa1 (nor-binaltorphimine) antagonists, respectively.     

Tramadol: pain relief by an opioid without depression of respiration

Two independent clinical trials were conducted simultaneously. In one, tramadol and pethidine were compared in 30 patients by patient-controlled analgesia during the first 24 h following abdominal surgery. The mean 24 h consumption of tramadol and pethidine was 642 mg and 606 mg respectively, giving a potency estimate of tramadol relative to pethidine of 0.94 (95% confidence interval 0.72-1.17). In the second trial, the effect on respiration of three doses of tramadol (0.5, 1.0, and 2.0 mg.kg-1) was compared with that of morphine sulphate (0.143 mg.kg-1) by intravenous injection during stable halothane anaesthesia. At approximately 1.5 times the equipotent dose, as estimated from the first trial, tramadol transiently depressed the rate of respiration but had no effect on end-tidal carbon dioxide tension. Morphine caused apnoea or considerable depression of ventilation. The results suggest that mechanisms other than opioid receptor activity play a significant role in the analgesia produced by tramadol.