Reversal by naloxone of spinal antinociceptive effects of fentanyl, ketocyclazocine and midazolam.

Experiments using measurement of electrical-current threshold as a nociceptive test in the skin of the tail and neck in rats demonstrated that fentanyl, ketocyclazocine and midazolam caused spinally mediated antinociception when the drugs were administered intrathecally via chronically implanted lumbar subarachnoid catheters. The benzodiazepine antagonist flumazenil selectively suppressed the midazolam response, indicating that this benzodiazepine exerted its segmental antinociceptive effect via spinal-cord benzodiazepine receptors. Naloxone blocked the responses to both opioids and also midazolam. The dose of naloxone which suppressed the midazolam response was similar to that required to suppress the response to the kappa-opioid agonist. We suggest that the segmental antinociceptive effects of fentanyl and midazolam are mediated via different pathways; the benzodiazepine exerts its antinociceptive action via a spinal-cord opioid pathway which does not involve mu-receptors.     

5-HT spinal antinociception involves mu opioid receptors: cross tolerance and antagonist studies

The antinociceptive effects of intrathecal 5-HT, fentanyl, ICI197067 and U50488H were assessed by electrical current nociceptive threshold and tail flick latency measurements. Equieffective doses of these agonists were then given intrathecally with a range of doses of naloxone or the highly selective mu opioid antagonist, beta- funaltrexamine. Antagonist dose-response curves were plotted. Other rats were made tolerant to either fentanyl or 5-HT by intrathecal injections of these drugs seven times daily and the antinociceptive effects of intrathecal fentanyl and 5-HT were assessed in each group. All intrathecal drugs caused spinally mediated antinociception in both tests. The antinociceptive effects of intrathecal 5-HT assessed by the electrical test (ECT) but not by tail flick latency (TFL) were suppressed by both opioid antagonists at doses similar to those required to suppress all of the effects of intrathecal fentanyl. The ED50 values were 0.22 (fentanyl, ECT), 0.25 (fentanyl, TFL) and 0.18 (5- HT, ECT) mumol kg-1 for naloxone and for beta-funaltrexamine 2.2 fmol (5-HT, ECT), the same order as that required to produce similar suppression of the antinociceptive effects of fentanyl (46 amol: fentanyl, ECT; 4.6 fmol: fentanyl, TFL) and very different from the ED50 for beta-FNA suppression of the antinociceptive effects of the kappa opioid, U50488H (5.88 pmol). Cross tolerance in both directions was demonstrated between intrathecal fentanyl and 5-HT in the electrical test but not in the tail flick test. We conclude that intrathecal 5-HT caused spinally mediated antinociceptive effects revealed by electrical current and tail flick latency tests. The antinociceptive effects in the electrical test involved spinal cord mu opioid receptors.      

Antinociceptive actions of intrathecal xylazine: interactions with spinal cord opioid pathways

We have studied rats with chronically implanted subarachnoid catheters. Xylazine, an alpha 2 adrenoceptor agonist, was injected intrathecally and nociceptive thresholds measured at two skin sites: the tail and the neck. Intrathecal xylazine (dose range 24.3-389 nmol) produced increases in electrical thresholds for nociception in the tail without any change in the neck; this observation suggested that the antinociceptive action of this drug was confined to the caudal part of the spinal cord responsible for tail innervation. The magnitude of this effect was dose-dependent. Tail flick latency also increased in these rats and the antinociceptive effects were antagonized in a dose- dependent manner by the selective alpha 2 adrenoceptor antagonist idazoxan (dose range 6.7-540 nmol). Intrathecal idazoxan also suppressed the increase in tail flick latency caused by the mu opioid agonist fentanyl (0.74 nmol) given intrathecally. This effect was also dose-dependent. The idazoxan dose-response curve for this suppression of fentanyl antinociception assessed with tail flick latency was the same as that for suppression of xylazine. In contrast, the antinociceptive effects of intrathecal xylazine were not affected by concurrent administration of opioid or GABAA antagonists. We conclude that intrathecal xylazine produced spinally mediated antinociceptive effects by combination with spinal cord alpha 2 adrenoceptors and that neither opioid nor GABA-containing propriospinal neurones were involved in the mediation of this effect. However, alpha 2 adrenoceptors in the spinal cord appear to be involved with antinociception produced by intrathecal fentanyl.      

Intrathecal midazolam and fentanyl in the rat: evidence for different spinal antinociceptive effects

The effects of intrathecal midazolam and fentanyl on electrical current threshold for pain were measured using stimulating electrodes in the neck and tail of rats with chronically implanted lumbar subarachnoid catheters. This involved the measurement of the minimum current (50 Hz 2 ms pulses 0-5 mA), which made the rat squeak when applied alternately to electrodes at each skin site. The responses measured in milliamperes were expressed as a number of times control readings. Equieffective doses of both midazolam and fentanyl produced a significant increase in electrical threshold for pain in the tail (mean +/- SEM 3.14 +/- 0.51 and 2.89 +/- 0.35: P less than 0.05; Wilcoxon sum rank test) in the absence of any change in the neck (mean +/- SEM 1.28 +/- 0.13 and 0.96 +/- 0.12, NS), thus demonstrating a spinal effect. Fentanyl caused a significant simultaneous increase in tail flick latency (mean +/- SEM 67.8 +/- 20.1%, P less than 0.05), but midazolam did not (mean +/- SEM 4.22 +/- 2.76%, NS). Intraperitoneal injections of naloxone (0.25 mg/kg) blocked the response to fentanyl in both tests and did not affect the response to midazolam. Intraperitoneal flumazenil (5 mg/kg) blocked the midazolam antinociceptive effect but did not affect the response to fentanyl in either test. Tail withdrawal in response to non-noxious stimulation was preserved in all animals with spinal analgesia, indicating that myelinated afferent and efferent pathways were still functioning. Righting reflex, coordination, motor power, and alertness were also preserved in the presence of both drugs. Both drugs caused spinally mediated antinociceptive effects that were qualitatively different.     

Analgesia mediated by spinal kappa-opioid receptors.

The results from 44 experiments performed on 13 rats with chronically implanted lumbar subarachnoid catheters are reported. ICI 197 067 produced dose-dependent segmental analgesic effects when measurement of electrical current threshold for pain was used as the nociceptive test. Ten microliters of intrathecal ICI 197 067 (0.06 mg ml-1; 1.5 nmol) caused a significant rise in the current threshold for pain in the tail of 1.56 +/- 0.04 x control (mean +/- SEM) but no significant change in pain threshold in the neck (1.03 +/- 0.03 x control). By contrast, simultaneous measurements of tail-flick latency in these animals revealed no significant rise in pain thresholds using this nociceptive test. Intraperitoneally administered naloxone produced a dose-dependent suppression of the spinally mediated analgesic effect produced by ICI 197 067; the ED50 for this effect was 0.79 mumol kg-1, a value very close to the ED50 for naloxone antagonism of ketocyclazocine spinally mediated analgesia. We conclude that ICI 197 067 produces spinally mediated analgesia by binding to spinal-cord kappa-opioid receptors.     

Antinociception by intrathecal midazolam involves endogenous neurotransmitters acting at spinal cord delta opioid receptors

Intrathecal midazolam causes antinociception by combining with spinal cord benzodiazepine receptors. This effect is reversible with doses of naloxone, suggesting involvement of spinal kappa or delta but not micrograms opioid receptors. The antinociceptive effects of intrathecally administered drugs in the spinal cord were demonstrated by measurements of the electrical current threshold for avoidance behaviour in rats with chronically implanted lumbar intrathecal catheters. A comparison was made of suppression by two opioid selective antagonists (nor- binaltorphimine (kappa selective) and naltrindole (delta selective)) of spinal antinociception caused by equipotent doses of opioids selective for different receptor subtypes (U-50488H (kappa), DSLET and DSBULET (delta), fentanyl (micrograms)) and the benzodiazepine midazolam. Nor- binaltorphimine selectively suppressed the effects of U-50488H but not midazolam or fentanyl. However, the delta selective antagonist, naltrindole, caused dose-related suppression of antinociception produced by both delta opioid agonists and midazolam with the same ED50 (0.5 nmol). We conclude that intrathecal midazolam caused spinally mediated antinociception in rats by a mechanism involving delta opioid receptor activation.      

Antinociceptive properties of neurosteroids: a comparison of alphadolone and alphaxalone in potentiation of opioid antinociception

In this study, we investigated the antinociceptive and sedative effects of the opioids fentanyl, morphine, and oxycodone given alone and in combination with two neurosteroids: alphadolone and alphaxalone. An open-field activity monitor and rotarod apparatus were used to define the sedative effects caused by opioid and neurosteroid compounds given alone intraperitoneally to male Wistar rats. Dose-response curves for antinociception were constructed using only nonsedative doses of these drugs. At nonsedating doses, fentanyl, morphine, and oxycodone all caused dose-dependent tail flick latency (TFL) antinociceptive effects. Because neither neurosteroid altered TFL, electrical current was used as the test to determine doses of neurosteroid that caused antinociceptive effects at nonsedative doses. Alphadolone 10 mg/kg intraperitoneally caused significant antinociceptive effects in the electrical test but alphaxalone did not. All three opioid dose-response curves for TFL antinociception were shifted to the left by coadministration of alphadolone even though alphadolone alone had no effect on TFL. Alphaxalone given alone had no antinociceptive effects at nonsedative doses and it had no effect on opioid antinociception. Neither neurosteroid caused sedative effects when combined with opioids. We conclude that coadministration of alphadolone, but not alphaxalone, with morphine, fentanyl, or oxycodone potentiates antinociception and that this effect is not caused by an increase in sedation.     

Electrophysiological evidence for an antinociceptive effect of ketamine in the rat spinal cord

Background : The dissociative anesthetic ketamine also has antinociceptive effects. The mechanism and the site of action of such effect of ketamine have been, however, elusive and controversial. The present study was conducted to examine the effect of systemically administered ketamine on spinal nociceptive transmission.
Methods : We investigated and compared the effects of ketamine (0.25-8 mg/kg) on the hamstring flexor reflex in intact, lightly anesthetized rats and spinally transected rats. The opioid receptor antagonist naloxone was used to examine the involvement of opioid receptors in the actions of ketamine. Finally, the effects of ketamine on dorsal horn neuronal activity to electrical stimulation of peripheral nerves were also studied.
Results : Ketamine caused similar dose-dependent depression of the hamstring flexor reflex recorded from spinally intact rats and from spinalized rats. Even the highest dose of ketamine failed to influence the monosynaptic reflex. The depressive effect of ketamine on the flexor reflex was not reversed by naloxone. Ketamine i.v. also exerted a relatively selective inhibition of the responses of dorsal horn wide-dynamic-range neurons to C-fiber input of electrical stimulation of the plantar nerve.
Conclusions : Our present results support the notion that ketamine can exert a direct antinociceptive effect in rat spinal cord. Moreover, the data indicated that the spinal antinociceptive effect of ketamine does not involve naloxone-sensitive opioidergic mechanisms.     

The effect of nitric oxide on fentanyl and haloperidol-induced catalepsy in mice

BACKGROUND AND OBJECTIVES: This study was designed to investigate the role of nitric oxide on catalepsy induced by fentanyl and haloperidol. METHODS: Male albino mice were treated either with fentanyl (0.1-0.2 mg kg-1, s.c.) or haloperidol (0.5-2 mg kg-1, i.p.). The non-selective nitric oxide synthase inhibitor, NG-nitro-L-arginine (10 mg kg-1, i.p.), selective neuronal nitric oxide synthase inhibitor, 7-nitroindazole (3 mg kg-1, i.p.), and nitric oxide donors, L-arginine (30-300 mg kg-1, i.p.) and D-arginine (30 mg kg-1, i.p.), were applied 20 min prior to fentanyl or haloperidol injection. A mu-opioid receptor antagonist naloxone (1 mg kg-1, i.p.) was also given in some groups. The cataleptic status of mice was assessed by placing animals in a rearing position in the cage. If the mouse maintained cataleptic posture for more than 20 s, it was scored as cataleptic and duration of catalepsy was expressed in terms of minutes. RESULTS: Both NG-nitro-L-arginine and 7-nitroindazole prolonged fentanyl-induced catalepsy (fentanyl: 3.6+/-0.8 min; fentanyl+NG-nitro-L-arginine: 77.4+/-14.6 min, fentanyl+7-nitroindazole: 56.0+/-10.4 min; n=6; P<0.01). This effect was reversed by L-arginine and naloxone, but not by D-arginine. Nitric oxide synthase inhibitors also prolonged the cataleptic action of haloperidol but to a lesser extent (haloperidol: 72.0+/-6.3 min; haloperidol+NG-nitro-L-arginine: 98.5+/-6.3 min, haloperidol+7-nitroindazole: 89.6+/-2.2 min; n=6; P<0.05). The prolongation of haloperidol-induced catalepsy with nitric oxide synthase inhibitors was not reversed by L-arginine. CONCLUSION: These results suggest a common mechanism between mu-opioid receptors and the nitric oxide system in the development of fentanyl-induced catalepsy in mice different from haloperidol-induced catalepsy.     

Antinociceptive interactions between alpha 2-adrenergic and opiate agonists at the spinal level in rodents

This study was undertaken to evaluate the antinociceptive interactions of alpha 2 adrenergic and opiate receptors at the spinal level. Morphine and clonidine were administered intrathecally (i.t.) by lumbar puncture to rats either alone or in the presence of either i.t. yohimbine, an alpha 2 antagonist, or systemic naloxone, an opioid antagonist. The effect of tolerance to systematically administered morphine on responses to i.t. morphine and clonidine was examined in mice. Antinociception was determined by observing the response to a clamp applied to the tail (Haffner test) in mice and by the tail-flick test in rats; log dose-response curves for antinociception were generated for morphine, clonidine, and each drug combination. Morphine and clonidine both produced dose-dependent antinociception when given i.t. in both species. The i.t. administration of yohimbine attenuated the antinociceptive effect of both clonidine and morphine, but naloxone attenuated only the response to morphine. Further, a sub-analgetic dose of i.t. clonidine potentiated the effect of i.t. morphine. In morphine-tolerant mice, i.t. morphine was not efficacious whereas clonidine retained full efficacy, although potency was slightly diminished. Thus, it appears that alpha 2 adrenoceptor-mediated antinociception is independent of opiate receptor mechanisms. Clinical use of intrathecal combinations of alpha 2 adrenergic and opiate receptor agonists to increase analgesia and use of intrathecal alpha 2 agonists for pain relief in patients tolerant to opiates might deserve evaluation.     

Preliminary report: the effect of flumazenil on the hypnotic dose of propofol in ddY mice

The present investigation dealt with the effect of simultaneous administration of flumazenil on the hypnotic activity of propofol using a behavioral model of ddY mice. The mixed solution of propofol and flumazenil was administered intravenously into the mice tail vein and the achievement of hypnosis was defined as the loss of the righting reflex. Flumazenil 0.2 mg.kg-1 significantly decreased the required dose of propofol for hypnosis (8.43 +/- 0.46 mg.kg-1) compared to the control group (10.55 +/- 0.55 mg.kg-1). The mixture with a pH-3.9 acetate buffer solution did not change the hypnotic dose of propofol (10.88 +/- 0.62 mg.kg-1). The results suggest that flumazenil might potentiate the hypnotic activity of propofol in ddY mice.     

Interaction of Intrathecally Infused Morphine and Lidocaine in Rats (Part I): Synergistic Antinociceptive Effects

Background: Synergistic antinociception of opioids and local anesthetics has been established in bolus injections but not in long-term use. The somatic and visceral antinociceptive effects of intrathecally infused morphine or lidocaine were characterized, and the nature of the interaction of those agents in rats was evaluated.

Methods: Intrathecal catheters were implanted in rats. Morphine (0.3 to 10 [micro sign]g [middle dot] kg-1 [middle dot] h-1), lidocaine (30-1,000 [micro sign]g [middle dot] kg-1 [middle dot] h-1), a combination of those, or saline was infused intrathecally at a constant rate of 1 [micro sign]l/h for 6 days. The tail flick and colorectal distension tests were used to measure the somatic and visceral antinociceptive effects, respectively. Nociceptive tests and motor function tests were repeated on days 1, 2, 3, 4, and 6. Isobolographic analysis was performed on the results of the tail flick test to determine the magnitude of the interaction.

Results: Intrathecally infused morphine produced dose-dependent antinociceptive effects in both the tail flick and the colorectal distension tests. Morphine showed a lower peak percentage maximum possible effect (%MPE) in the colorectal distension test than in the tail flick test. Intrathecal lidocaine also produced dose-dependent antinociceptive effects. Lidocaine infusion at 1,000 [micro sign]g [middle dot] kg-1 [middle dot] h-1 caused motor impairment. Coinfusion of morphine 0.3 [micro sign]g [middle dot] kg-1 [middle dot] h-1 and lidocaine 200 [micro sign]g [middle dot] kg-1 [middle dot] h-1, which had no effects by themselves, significantly increased the percentage maximum possible effects (P < 0.01). Coinfused lidocaine potentiated the duration and the magnitude of morphine antinociception. Isobolographic analysis of the tail flick test on day 1 showed a synergistic interaction between morphine and lidocaine.     

Anesthetic interactions of midazolam and fentanyl: is there acute tolerance to the opioid?

The anesthetic effects and interactions of midazolam and fentanyl were determined in terms of their reduction of enflurane MAC in dogs, and the effects of their specific antagonists were also investigated. Control enflurane MAC was determined by the tail clamp method in 18 mongrel dogs. Each animal then received an iv loading dose of midazolam followed by a constant infusion at 9.6 micrograms.kg-1.min-1 designed to produce a stable enflurane MAC reduction of approximately 40%, and enflurane MAC was determined following a 60-min observation period during which time the midazolam concentration in plasma stabilized. Fentanyl was then administered in a series of three incremental loading doses (15, 30, and 225 micrograms/kg) and infusions (0.05, 0.2, and 3.2 micrograms.kg-1.min-1) designed to produce enflurane MAC reductions of 30%, 50%, and 65%, respectively. Enflurane MAC was again determined following a 60-min observation period for each new infusion. In nine dogs after the fourth determination of enflurane MAC, fentanyl was discontinued and 1 mg/kg naloxone was administered iv every 10 min until enflurane MAC was determined for the last time. In the other nine dogs, midazolam was discontinued and 1.5 mg/kg flumazenil (RO 15-1788) was administered and enflurane MAC determined for the last time. The midazolam concentration in plasma remained stable at 414 +/- 134 ng/ml throughout the study, and in the absence of fentanyl reduced enflurane MAC by 40 +/- 10% (mean +/- SD). The addition of fentanyl produced significant further reductions in enflurane MAC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies of the pharmacology and pathology of intrathecally administered 4-anilinopiperidine analogues and morphine in the rat and cat

In rats, intrathecal alfentanil, lofentanil, sufentanil, fentanyl, and morphine produced dose-dependent elevations in the hot-plate and tail-flick latencies and a powerful suppression of the writhing response. The slopes of the monotonic dose-response curves for the five opioids did not differ significantly. In terms of the hot-plate ED50 after intrathecal injection, the order of potency was as follows: lofentanil (210), sufentanil (29), fentanyl (3), morphine (1), and alfentanil (1). Comparable results were observed in the tail flick. The duration of action was proportional to dose. However, at doses that produced an equal magnitude of inhibition, the duration of action was lofentanil greater than morphine greater than sufentanil greater than alfentanil greater than or equal to fentanyl. Systemically administered naloxone (0.03-1 mg/kg, sc) resulted in dose-dependent antagonism of the antinociceptive effect of intrathecal morphine, fentanyl, alfentanil, and sufentanil. In contrast, intrathecal lofentanil was extremely resistant to antagonism by naloxone. In cats, similar dose-dependent blockade of the thermally evoked skin-twitch response was observed after intrathecal morphine, sufentanil, alfentanil, and fentanyl. As in the rat, the slope of the monotonic dose-response curves did not differ. The relative potency and duration of action after equipotent intrathecal doses were similar to those observed in the rodent. These results suggest that sufentanil, alfentanil, and fentanyl exert their analgesic effects in vivo at a spinal cord site that has properties comparable to those of the site acted upon by morphine. Except for catalepsy in rats, no major behavioral dysfunctions were noted at the ED50 dose of any of the drugs administered. No abnormal morphologic effects of acutely or chronically administered alfentanil and sufentanil were seen, aside from an inflammatory reaction secondary to catheter placement.     

Barbiturates inhibit stress-induced analgesia

The effect of pentobarbitone and thiopentone on stress-induced analgesia was studied in 40 male Sprague-Dawley rats. Antinociception was determined by measuring motor reaction threshold to the noxious pressure on the tail with the use of an "Analgesymeter." Stress was induced by placement of a clamp on the hind paw. The stress procedure was found to cause an increase in reaction threshold, which was partially suppressed by naloxone 0.5 mg X kg-1. Pentobarbitone in a subanaesthetic dose of 25 mg X kg-1, SC, almost completely abolished the stress-induced increase in the reaction threshold (an increase in reaction threshold from 329 +/- 33 g to 486 +/- 62 g in control group, and from 250 +/- 26 g to 273 +/- 35 g in pentobarbitone group, p less than 0.02 for the difference in the threshold changes). Thiopentone used in a dose of 25 mg X kg-1, IV, caused a loss of the righting reflex for 37 +/- 10 minutes; stress procedure applied ten minutes after regaining the righting reflex did not cause any increase in the reaction threshold (with an increase in the reaction threshold in control group from 355 +/- 50 g to 540 +/- 26 g, p less than 0.001 for the difference between the groups). The results suggest that the barbiturates in subanaesthetic doses inhibit stress-induced analgesia. Thiopentone used in an anaesthetic dose has the potential for inhibition of stress-induced analgesia in the period of recovery from anaesthesia.     

Less than additive antinociceptive interaction between midazolam and fentanyl in enflurane-anesthetized dogs

The anesthetic interactions of midazolam and fentanyl were determined in terms of enflurane MAC reduction in dogs. In part 1, 8 animals received an intravenous (iv) loading dose of fentanyl followed by a constant infusion at 0.05 micrograms.kg-1.min-1 to produce a stable enflurane MAC reduction of approximately 20%. Midazolam was then administered in a series of three incremental loading doses and infusions (2.4, 9.6, and 28.8 micrograms.kg-1.min-1 previously determined to produce enflurane MAC reductions of approximately 30, 45, and 60%, respectively. Enflurane MAC was determined for each infusion. Then fentanyl was discontinued; naloxone 1 mg/kg was administered; and enflurane MAC was determined. In part 2, six dogs received a loading dose and a continuous infusion of fentanyl (0.2 micrograms.kg-1.min-1) designed to produce a stable enflurane MAC reduction of approximately 40%. A series of two incremental loading doses and infusions of midazolam (2.4 and 28.8 micrograms.kg-1.min-1) were added, and MAC determinations were repeated at each infusion rate. Then midazolam was discontinued; flumazenil (RO 15-1788) 1.5 mg/kg was administered; and enflurane MAC was determined. The fentanyl concentrations in plasma remained stable at 1.0 +/- 0.3 ng/ml (mean +/- standard deviation [SD], part 1) and 3.1 +/- 0.5 ng/ml (part 2) throughout the study and, in the absence of midazolam, reduced enflurane MAC by 28 +/- 11 and 44 +/- 5%, respectively. The addition of midazolam produced significant further reductions in enflurane MAC, but the reductions were less than those predicted on the basis of an additive interaction. Naloxone returned enflurane MAC reduction to that expected for midazolam alone (part 1).(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of fentanyl upon cerebral high-energy metabolites, lactate, and glucose during severe hypoxia in the rat

The effects of intravenous administration of high-dose fentanyl (100 micrograms.kg-1, loading dose followed by an infusion of 200 micrograms.kg-1.h-1) were compared with those of a barbiturate (pentobarbital sodium 25 mg.kg-1, intraperitoneal) or hypothermia (rectal temperature 32 degrees C) on changes in cerebral cortical tissue levels of adenosine triphosphate (ATP), phosphocreatine (PCr), lactate, and glucose in severely hypoxemic rats (PaO2 13-23 mmHg for 20 min) with unilateral (left side) carotid ligation (10-12 animals in each group). Ligation of the carotid artery alone produced no change in brain high-energy metabolites, lactate, or glucose. The control values on the ligated side (nitrous oxide, 70%, + normoxia group) for cortical ATP, PCr, lactate, and glucose were 2.86 +/- 0.09 (mumol.g-1 wet weight, mean +/- 1 SE), 3.83 +/- 0.11, 1.68 +/- 0.21, and 3.29 +/- 0.47, respectively. Hypoxia (nitrous oxide, 70%, + hypoxia group) produced a significant (P less than 0.05) decrease in ATP (1.83 +/- 0.37) and PCr (1.93 +/- 0.48) and an increase in lactate (15.8 +/- 1.77) compared with the normoxic group, whereas brain glucose was not significantly changed (1.97 +/- 0.65). Fentanyl (fentanyl + hypoxia group) did not prevent the deleterious effects of hypoxia on cortical high energy metabolites (ATP, 2.0 +/- 0.27; PCr, 2.24 +/- 0.3) or lactate (19.33 +/- 3.16); however, fentanyl caused no alteration in high-energy cerebral metabolite concentrations in normoxic rats, nor did fentanyl produce a significant difference in brain tissue glucose or lactate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of naloxone infusion on analgesia and respiratory depression after epidural fentanyl

The efficacy of two dosage regimens of intravenous naloxone were compared to avoid nonrespiratory side effects and respiratory depression and yet to preserve analgesia (maximum tolerance to periostial pressure over the tibia) after administration of 200 micrograms epidural fentanyl. Three groups of eight patients were studied: group 1 patients received a loading dose of 0.4 mg IV naloxone followed by naloxone infusion at a rate of 10 micrograms.kg-1.hr-1. Group II patients received a loading dose of 0.2 micrograms naloxone followed by a naloxone infusion at a rate of 5 micrograms.kg-1.hr-1. Group III patients received a saline infusion at a rate of 20 ml/hr. Epidural fentanyl significantly increased tolerance to periostial pain in all three groups (respectively, +38 +/- 20%, +36 +/- 16%, and +35 +/- 14%) (mean +/- SD; P less than 0.05). The naloxone infusion significantly reduced this effect in groups I and II, respectively, -40 +/- 20% and -37 +/- 28% below prenaloxone levels) (P less than 0.05). Nonrespiratory side effects were also reversed in groups I and II. In group III, neither periostial analgesia nor nonrespiratory side effects were affected. The baseline slopes of VE/PETCO2 were 2.34 +/- 1.01, 2.14 +/- 0.66, and 2.68 +/- 1.14 L.min-1.mm Hg-1, respectively, in groups I, II, and III. Epidural fentanyl significantly decreased the slope below baseline levels in each group: -21 +/- 16%, -22 +/- 17%, and -19 +/- 32%, respectively, in groups I, II and III.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absence of agonistic or antagonistic effect of flumazenil (Ro 15-1788) in dogs anesthetized with enflurane, isoflurane, or fentanyl-enflurane

This study determined the effects of flumazenil on the anesthetic requirements (MAC) of the dog for isoflurane (group 1; n = 6), enflurane (group 2; n = 7), and a combination of fentanyl-enflurane (group 3; n = 6). Control MAC in each group was determined by the tail-clamp method. Each animal in groups 1 and 2 received four iv incremental doses of flumazenil: 0.5, 1.0, 1.5, and 4.5 mg/kg, and isoflurane MAC or enflurane MAC was determined after each dose. The animals in group 3 received a loading dose and a continuous infusion of fentanyl 0.8 micrograms.kg-1.min-1 over 8 h, and enflurane MAC was determined four times during this experimental period. After the fourth enflurane MAC determination in each animal of group 3, a single iv dose of flumazenil 1.5 mg/kg was injected and enflurane MAC was then determined for the last time. In the incremental doses administered, flumazenil did not demonstrate any agonistic or antagonistic interaction with isoflurane, enflurane, or the fentanyl-enflurane combination. In group 3, plasma fentanyl concentrations remained stable at 12.5 +/- 3.0 ng/ml (mean +/- SD) throughout the experiment and reduced enflurane MAC by 60 +/- 8%. The addition of flumazenil changed neither the fentanyl concentration in plasma (12.2 +/- 3.8 ng/ml) nor its reduction of enflurane MAC (61 +/- 7%). In conclusion, the absence of effect of flumazenil on the MAC of enflurane, isoflurane, or a fentanyl-enflurane combination suggests that they do not interact with the benzodiazepine receptor.     

Interaction between midazolam and serotonin in spinally mediated antinociception in rats

Purpose  Intrathecal administration of serotonin (5-HT) is antinociceptive through the involvement of spinal cord γ-aminobutyric acid (GABA) receptors. Therefore, 5-HT would interact with the GABA agonist, midazolam, which is well known to exert spinally mediated antinociception in the spinal cord. The present study investigated the antinociceptive interaction between spinally administered 5-HT and midazolam, using two different rat nociceptive models. Methods  Sprague-Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and paw flinches induced by formalin injection after the intrathecal administration of midazolam or 5-HT, or the midazolam/ HT combination. The effects of the combination were tested by isobolographic analysis, using the combination of each 1, 1/2, 1/4, 1/8, and 1/16 of the 50% effective dose (ED50). The total fractional dose was calculated. Behavioral side effects were also examined. Results  5-HT alone and midazolam alone both showed dose-dependent antinociception in both the tail flick test and the formalin test. The ED50 of the combination was not different from the calculated additive value either in the tail flick test or in phase 2 of the formalin test, but it was significantly smaller than the calculated additive value in phase 1 of the formalin test. The total fractional dose value was 0.90 in the tail flick test, 0.093 in phase 1 of the formalin test, and 1.38 in phase 2 of the formalin test. The agitation, allodynia, or motor disturbance observed with either agent alone was not seen with the combination treatment. Conclusion  The antinociceptive effects of intrathecal midazolam and 5-HT were additive on thermal acute and inflammatory facilitated stimuli, and synergistic on inflammatory acute stimulation.