Antinociceptive properties of neurosteroids II. Experiments with Saffan and its components alphaxalone and alphadolone to reveal separation of anaesthetic and antinociceptive effects and the involvement of spinal cord GABA(A) receptors.

Studies have shown that the steroid anaesthetic alphaxalone positively modulates gamma-aminobutyric acid (GABA) receptors in vitro. It has also been reported that positive modulation of GABA(A) receptors in the rat spinal cord can produce antinociception in vivo. This present study looks at the interaction of an intraperitoneal injection (i.p.) of the steroid anaesthetic combination Saffan (alphaxalone 9 mg/ml, alphadolone acetate 3 mg/ml) with GABA(A) receptors in the spinal cord. Full recovery from anaesthesia induced by Saffan 2 ml/kg i.p., as assessed by the rotarod test, occurred after 28.78 +/- 0.86 min. Residual antinociceptive effects were assessed by application of electrical current at two skin sites (neck and tail) and also tail withdrawal from noxious heat. Residual antinociception was observed at both skin sites assessed by the electrical test but not when assessed by noxious heat. The antinociceptive effects in the tail but not the neck were suppressed by intrathecal administration of GABA(A) antagonists (bicuculline and SR-95531). In a separate group of experiments alphaxalone and alphadolone were given i.p. individually at the same doses that were given when formulated in Saffan. Alphaxalone produced sedative and anaesthetic effects with no antinociception. Alphadolone caused no sedation but it did cause antinociceptive effects equal in magnitude to those produced by Saffan. We conclude that Saffan produces antinociception in rats when given i.p. by an interaction with spinal GABA(A) receptors. Furthermore, this antinociception is due to the alphadolone content of the neurosteroid anaesthetic and not the alphaxalone.

Spinal and supraspinal components of opioid antinociception in streptozotocin induced diabetic neuropathy in rats.

This study investigated the antinociceptive effect of opioids given via intraperitoneal and intrathecal routes in a diabetes-induced neuropathic pain model in rats. Streptozotocin induced diabetes in 91% of juvenile male Wistar rats at the dose of 150 mg/kg (75 mg/kg intraperitoneal on 2 successive days). When compared with younger weight-matched saline treated rats, the diabetic rats developed hyperalgesia assessed by the paw pressure nociceptive test. Nociceptive thresholds and responses to fentanyl in all nociceptive tests in these younger normal rats were the same as those described previously for older normal rats. Fentanyl (10-100 microg/kg, i.p.) produced a dose-related antinociceptive effect in both neuropathic (n=6-8) and non-neuropathic (n=6-8) rats in electrical current, paw pressure and tail flick nociceptive tests. Higher doses of fentanyl were needed in neuropathic animals to achieve similar antinociceptive effects to those in non-neuropathic animals. Intrathecal injections of fentanyl (0.05-0.5 microg) in non-neuropathic rats, produced a spinally-mediated, dose-related antinociceptive effect assessed by all tests. In contrast, intrathecal administration of fentanyl that confined the drug action to the spinal cord produced little antinociceptive effect in neuropathic rats in all three tests. These experiments suggest that supraspinal mu opioid receptors are responsible for the antinociceptive effect of opioids in this model of neuropathic pain and that spinal cord opioid systems are in some way rendered ineffective for antinociception assessed with noxious heat, electrical and pressure stimuli.

Antinociceptive properties of neurosteroids I. Spinally-mediated antinociceptive effects of water-soluble aminosteroids.

Four water-soluble aminosteroid intravenous anaesthetic agents (ORG 20380, 20549, 21047 and 20599) were investigated for antinociceptive properties following intrathecal injection in rats. Two compounds, ORG 20380 and 20549, produced spinally-mediated antinociception assessed by tail flick and electrical current nociceptive tests. These effects were dose-related and suppressed by concurrent administration of the GABA(A) receptor antagonist, bicuculline. ORG 21047 and 20599 caused no antinociceptive effects when given intrathecally. Experiments in which nociceptive thresholds were measured after intravenous injections of ORG 20549 showed that subanaesthetic doses of this compound caused antinociceptive effects revealed by both nociceptive tests. This was equal in magnitude to that obtained with intrathecal administration of the same drug. We conclude that ORG 20380 and 20549 produce spinally-mediated antinociception by combination with spinal cord GABA(A) receptors. These spinal receptors are different from the GABA(A) receptors responsible for the anaesthetic effects of these drugs.

Convulsive thresholds in mice during the recovery phase from anaesthesia induced by propofol, thiopentone, methohexitone and etomidate.

1. Convulsive thresholds were measured with intravenous pentylenetetrazol in mice during the recovery phase after intravenous anaesthetic doses of propofol (10 and 20 mg kg-1), thiopentone (30 mg kg-1), methohexitone (10 mg kg-1), and etomidate 3 mg kg-1). 2. The convulsive threshold rose after each agent, indicating an anticonvulsant action for all the drugs tested; this declined to control values with initial half times of: 1.56 min (propofol 10 mg kg-1); 1.03 min (propofol 20 mg kg-1): 1.02 min (methohexitone); 3.35 min (etomidate); 13.7 min (thiopentone). 3. At no time during the recovery phase of any agent did the convulsive threshold fall below control values, which might indicate an epileptogenic effect of the drug. 4. The threshold was depressed below control values by intravenous administration of Ro 15-4513, a partial inverse agonist at the benzodiazepine receptor, thus indicating the ability of this pentylenetetrazol test to demonstrate a proconvulsant effect. 5. We conclude that the abnormal movements or convulsions associated with recovery from anaesthesia with short-acting intravenous anaesthetics may not be the result of an intrinsic proconvulsant action of the drugs.

Propofol: effects on indices of cerebral ischemia.

The effects of propofol given before and during a period of profound hypotension that caused incomplete global cerebral ischaemia were investigated in anaesthetised cats. Cortical cerebral blood flow, extracellular fluid pH, potassium and calcium ion activities, and electroencephalogram were recorded. Neuropathological outcome was also assessed. Propofol-treated animals had higher cerebral blood flows than control animals after the period of hypotension (p <0.05); they also had better correction of extracellular fluid acidosis and hyperkalaemia (p <0.01) and a late improvement in calcium ion activity (p <0.05). Neuropathological outcome was not significantly different between the groups.

Vascular effects of propofol: smooth muscle relaxation in isolated veins and arteries.

Isolated hepatic portal veins and aorta taken from the rat were used to investigate the direct action of the intravenous anaesthetic propofol. This compound is known to produce a fall in blood pressure in man and animals and it has been suggested that the hypotension may result from a direct vasodilator action on the veins and arterioles. In our experiments propofol caused a dose related decrease of potassium-induced tone in both types of blood vessel. However, the concentrations required to produce this effect in the experiments on veins were significantly lower than those required to produce similar changes in the isolated artery preparation. We conclude that this direct action may contribute towards the hypotensive effects of propofol.

Acute postoperative pain: logical treatment by drug combinations.

Most patients who undergo major surgery suffer severe postoperative pain. This fact has been known by many generations of health care workers, and highlighted in the report of the Working Party organised jointly by the Colleges of Surgeons and Anaesthetists of Great Britain. Although effective therapies exist they are frequently not used in an effective manner. Everyone knows that enough morphine will abolish pain. However, the doses of a drug such as morphine required to completely relieve a patient's pain may cause several side effects or even death. There is an enormous variability between patients and operations in morphine requirements to relieve postoperative pain. Many patients are not given adequate doses for fear of inducing side effects. It is obvious that provision of postoperative pain relief tailored to each individual patient's needs requires more than a 'prn Omnopon' prescription. The level of pain needs to be monitored in much the same way as we would monitor blood pressure or urine output postoperatively and health workers who understand these readings and the appropriate treatment should review them.

Postoperative recovery rooms. Staffing and facilities in three regions in the United Kingdom.

Postoperative recovery rooms have been used in the United Kingdom for just over 30 years. Anaesthetic and surgical practices have improved during this time but the clinical problems encountered are unchanged essentially. Several surveys have reviewed complications that occur; the most common causes of postoperative morbidity and mortality are still cardiovascular and respiratory problems, the latter particularly of the upper airway. In contrast there are no data available on the standard of staff and equipment in recovery rooms. The results of a survey of this aspect of postoperative recovery rooms in hospitals in Wessex, North West Thames and Yorkshire Regional Health Authorities are reported. Particular effort was made to define the facilities available. The results indicate that 70% of hospitals do not provide staffing levels and facilities which meet recommendations of the Association of Anaesthetists of Great Britain and Ireland. The implications of these findings with regard to anaesthetic morbidity and mortality are discussed.

Spinal cord effects of drugs used in anaesthesia.

1. Measurement of nociceptive thresholds at two skin sites in rats with chronic intrathecal catheters has allowed study of drug actions demonstrated to be at spinal level. 2. Using this preparation we have demonstrated segmental antinociceptive effects following intrathecal administration of agonists selective for benzodiazepine receptors, mu, kappa and delta opioid receptors, 5-hydroxytryptamine (5-HT) receptors and alpha adrenoceptors. 3. Such effects were dose related and were suppressed by appropriate selective antagonists. 4. Antagonist dose-response curves have been constructed for suppression of antinociceptive effects of various agonists. This has revealed complex interactions between spinal systems; for example midazolam produces its actions by activating an opioid system involving delta receptors.

Antinociceptive role of 5-HT1A receptors in rat spinal cord.

BACKGROUND: Intrathecal administration of 5-hydroxytryptamine (5-HT) is antinociceptive to noxious heat and electrical stimuli. The contributions of different receptor subtypes to the antinociceptive effects of 5-HT are controversial. The main reasons for this are the poor receptor subtype selectivity of some agonist drugs and the difficulty of restricting drug action to the spinal cord in some experimental paradigms. This study investigated the roles of different 5-HT receptor subtypes involved in the spinal cord control of the nociception produced by these two nociceptive testing paradigms. METHODS: Tail-flick latency and electric current threshold for nociception were measured in an acute pain model that allowed the study of the antinociceptive effects of intrathecally administered drugs that were due to actions of these drugs at spinal cord receptors. Experiments were performed in male Wistar rats with chronically implanted lumbar subarachnoid catheters. Dose-response curves for spinally mediated antinociceptive effects of agonists selective for 5-HT receptor subtypes were constructed. RESULTS: The 5-HT1 agonist 1-(3-chlorophenyl)-piperazine dihydrochloride caused a dose-dependent antinociceptive effect, measured by both nociceptive tests. However, 8-hydroxy-DPAT (selective 5-HT1A agonist) produced antinociception assessed by electric current but not tail flick. A 5-HT1A-selective antagonist, 4-[3-(benzotriazol-1-yl)propyl]-1-(2-methoxyphenyl)-piperazine, reversed the antinociception in the electrical test produced by both of these agonists but the tail-flick latency effects after intrathecal 1-(3-chlorophenyl)-piperazine were not suppressed by this antagonist. CONCLUSIONS: We conclude that 5-HT1A receptors in the spinal cord are involved in the nociceptive mechanisms assessed by noxious electrical stimuli. Other 5-HT1 receptors (non 5-HT1A receptors) are involved in the spinally mediated antinociception assessed by thermal noxious stimuli.

Hypertrophic obstructive cardiomyopathy in combination with a prolapsing mitral valve. Anaesthesia for surgical correction with propofol.

The anaesthetic management of a 27-year-old woman who presented for surgical correction of hypertrophic obstructive cardiomyopathy and mitral valve prolapse is described. The rationale for using propofol in a total intravenous anaesthetic technique is discussed.

Cardiovascular effects of propofol in the anaesthetized dog.

This study was designed to investigate if propofol produced cardiovascular effects by direct actions or by indirect actions secondary to depression of the central nervous system. Experiments were performed on chloralose anaesthetized dogs in which all neurogenic cardiovascular reflexes were abolished by bilateral vagotomy and common carotid ligatures, in combination with i.v. bretylium and propranolol. Bolus doses of propofol followed by infusions at rates up to 160 mg kg-1 h-1 produced blood concentrations of propofol from 1.99 to 112 micrograms ml-1. Infusions of hydroxyethyl starch given to maintain central venous pressures and pulmonary artery occlusion pressures at control values were used as an index of changes in capacitance. Blood concentrations of propofol less than 10 micrograms ml-1 caused an increase in mean capacitance of 8.0 (SEM 1) ml kg-1 with no significant changes in systemic vascular resistance, pulmonary vascular resistance or inotropic state of the heart. We conclude that anaesthesia with propofol may be accompanied by decreased cardiac output secondary to reduction in preload by a direct venodilator effect. Our experiments indicate that cardiac output and arterial pressure are preserved well at normal anaesthetic blood concentrations of propofol if the preload is maintained.

Intrathecal midazolam in the rat: evidence for spinally-mediated analgesia.

This study investigated the possible analgesic effect of midazolam as a result of interruption of those spinal cord pathways taken by pain afferents. Experiments were performed on 15 male Wistar rats with chronically implanted lumbar subarachnoid catheters. The threshold for pain induced by brief passage of electric current between pairs of electrodes placed on the tail and the skin of the neck was measured before and after subarachnoid injections of midazolam. Intrathecal midazolam caused a significant (P less than 0.02) increase in the threshold for pain in the tail, but not in the neck; this response was not produced by intrathecal injections of vehicle and was blocked by prior intraperitoneal injections of the benzodiazepine antagonist RO 15-1788. We also performed experiments on frog sciatic nerves which showed that midazolam did not have a local anaesthetic action. We conclude that intrathecal midazolam causes spinally-mediated analgesia by binding to benzodiazepine receptors in the spinal cord.

The effects of intrathecal midazolam on sympathetic nervous system reflexes in man--a pilot study.

Nine patients were given intrathecal injections of midazolam (dose 0.3-2 mg dissolved in 3 ml 5% dextrose). No changes in motor power or general sensation were produced. Resting heart rate and blood pressure were unchanged and normal valsalva manoeuvres were elicited 30 min post-injection. Cardiovascular responses were provoked at a light plane of anaesthesia by intubation of the trachea and manipulation of peritoneum and bowel but not by surgical incision of the skin. Intrathecal administration of midazolam relieved post-operative pain of somatic origin but not of visceral origin. It is concluded that intrathecal midazolam in the dosage used interrupts somatic nociceptive afferent pathways but not abdominal visceral nociceptive afferent pathways.

Antinociceptive properties of propofol: involvement of spinal cord gamma-aminobutyric acid(A) receptors.

In this study, we investigated the interaction of propofol (a compound used widely as an intravenous anesthetic) with gamma-aminobutyric acid(A) (GABA(A)) and delta opioid receptors at the level of the spinal cord. Nociceptive thresholds were measured in rats through the use of electrical current testing (ECT) and tail-flick latency. Full recovery from sedation occurred 36.3 +/- 1.7 min (mean +/- S.E.M.; n = 20) after 40 mg/kg propofol i.p. Forty minutes after administration, there was residual antinociception when assessed by ECT but not when assessed by noxious heat. The ECT antinociceptive effects of propofol at tail but not neck sites were suppressed by intrathecal injection of the GABA(A) antagonists bicuculline and SR-95531 and the delta opioid antagonist naltrindole. These results suggest that there is an interaction between propofol and antagonists at receptors in the caudal segments of the spinal cord responsible for tail innervation. Antagonist dose-response curves were compared with those for suppression of intrathecal midazolam-induced antinociception. All intrathecal antagonists reversed the antinociceptive effect of propofol with the same dose-response curves as those previously obtained for suppression of the effect of intrathecal midazolam. We conclude that propofol, when given intraperitoneally, produces antinociception in rats through an interaction with spinal GABA(A) receptors. This combination leads to activation of a spinal cord system involving a delta opioid receptor; the same mechanisms involved with midazolam-induced spinal antinociception.

Antinociceptive properties of neurosteroids III: experiments with alphadolone given intravenously, intraperitoneally, and intragastrically.

The veterinary neurosteroid anaesthetic Saffan has the same formulation as Althesin now withdrawn from human use and is a mixture of two neurosteroids, alphadolone, and alphaxalone. The molecular structures of these two pregnanes and their properties as i.v. anaesthetics were reported to be similar. Preliminary experiments showed that alphadolone caused powerful antinociceptive effects without sedation when given i.p. In this study, alphadolone was given to rats (weight 100-200 g) i.v., i.p., and intragastrically. I.v. injections of alphadolone (25 mg kg(-1)) caused anaesthesia and sedation, whereas i.p. (0.1-100 mg kg(-1)) and intragastric administration (750 mg kg(-1)) produced no such effects. Intragastric alphadolone caused antinociceptive effects assessed with the electrical current threshold test (response 2.2 x pre-drug control values) without sedation. These effects were reversed at the level of the spinal cord by intrathecally-administered bicuculline (10 pmol). We conclude that a metabolite of alphadolone acetate produced in the liver leads to antinociceptive effects after i.p. and intragastric administration of the parent compound. This antinociception involves spinal cord GABA(A) receptors, even though the drug was administered via a non-spinal route.

Reversal of streptokinase-induced bleeding with aprotinin for emergency cardiac surgery.

Two patients requiring emergency cardiac surgery following the administration of streptokinase are described. In each case aprotinin was given to counteract the haemorrhagic effects of the streptokinase.

Potentiation by ketamine of fentanyl antinociception. I. An experimental study in rats showing that ketamine administered by non-spinal routes targets spinal cord antinociceptive systems.

BACKGROUND: Ketamine has been found to exert antinociceptive effects in animals and to be analgesic at subanaesthetic doses in humans. This study was designed to investigate the involvement of spinal cord mechanisms in the potentiation of opioid analgesia by parenteral non-spinal administration of ketamine. METHODS: Thresholds for nociception were measured in an acute pain model in rats that allowed identification of antinociceptive effects due to drug action in the spinal cord. Dose-response curves for the antinociceptive effects of ketamine alone and ketamine in conjunction with the mu opioid fentanyl were constructed. RESULTS: Intraperitoneal ketamine up to 3.75 mg kg(-1) caused no sedative or antinociceptive effects and intrathecal ketamine caused dose-dependent, spinally mediated antinociceptive effects. Injections of ketamine doses that caused no antinociceptive effects when given alone (intrathecal 25 microg and intraperitoneal 3.75 mg/kg) significantly increased spinally mediated antinociception produced by intrathecal fentanyl injections when assessed using noxious heat (tail-flick test) but not when assessed by noxious electrical current (electrical current threshold test). CONCLUSIONS: We conclude that ketamine can potentiate the effects of fentanyl by an interaction at the level of the spinal cord even when ketamine is given via a non-spinal route of administration.

Supraspinal and spinal cord opioid receptors are responsible for antinociception following intrathecal morphine injections.

BACKGROUND AND OBJECTIVE: The clinical practice of spinal morphine administration for pain relief is based on observations in animals that opioid receptors exist in the spinal cord and intrathecal injections of opioids in those species (mostly rats) lead to antinociceptive effects. Clinicians are well aware that administration of spinal opioids is associated with side-effects, such as nausea and respiratory depression, that indicate supraspinal spread of the drug administered. Those observations call into question how much of the observed pain relief is due to action of the drug in the brain. This study investigated the spinal cord actions of morphine given intrathecally to rats in a model that allows investigation of drug-receptor interaction at the spinal cord level. Experiments were performed on male Wistar rats with chronically implanted lumbar subarachnoid catheters. METHODS: Nociceptive thresholds were measured in rats given morphine intrathecally alone and in combination with intrathecal injections of selective opioid receptor antagonists: beta-funaltrexamine (mu), naltrindole (delta) and nor-binaltorphimine (kappa). RESULTS: Intrathecal morphine caused dose-related antinociceptive effects that were reversed totally by naloxone. Intrathecal beta-funaltrexamine and naltrindole did not reverse the effects of intrathecal morphine. However, intrathecal nor-binaltorphimine did reverse the electrical current threshold effects of morphine but not tail flick latency. CONCLUSIONS: Antinociception following intrathecal morphine involves spinal and supraspinal opioid receptors. The tail flick effect described in rat experiments involves actions at opioid receptors in the brain that override any action that may be caused by combination of morphine with mu-opioid receptors in the spinal cord.