Naaznin Samanani

Hyperalgesia during sedation: effects of barbiturates and propofol in the rat.

Subhypnotic doses of thiopentone are considered to possess antianalgesic or hyperalgesic properties. In this study, we have tested the hypothesis that the coincidence of sedation and hyperalgesia is a property of both barbiturate and non- barbiturate anaesthetic agents. In a randomized, prospective, blinded study, the effects of slow (20 min) iv infusions of thiopentone, pentobarbitone, methohexitone or propofol on nociceptive threshold were measured in rats by tail pressure analgesimetry and compared with saline- infused control animals. Nociceptive thresholds were correlated with measurements of plasma drug concentrations and behavioural assessments. Comparison of pre- infusion nociceptive threshold with the lowest threshold obtained during drug infusion revealed decreases in all four treatment groups. As a percentage of the pre- infusion values, the decreases were: thiopentone: 42.5% (P < 0.001), pentobarbitone : 27.8% (P = 0.014), methohexitone: 24.9% (P = 0.013), propofol: 21.6% (P = 0.006). There were no changes in nociceptive threshold in the control groups. The relationship between nociceptive threshold and plasma drug concentration was usually characterized by an initial decline followed by a rise in nociceptive threshold as the plasma concentration and degree of sedation increased. The results support the hypothesis that hyperalgesia is a property of different anaesthetic agents when administered at sub- hynotic concentrations.RésuméOn considère que les doses sous- hypotiques de thiopentone possèdent des propriétés antianalgésiques ou hyperalgésiques. Cette étude vérifie l’hypothèse selon laquelle la coïncidence de la sédation avec l’hyperalgie constitue à la fois une propriété des agents anesthésiques barbituriques et des non barbituriques. Au cours d’une élude randomisée, prospective et à l’aveugle, les répercussions sur le seuil nociceptif d’une perfusion lente (20 min) de thiopentone, pentobarbitone, méthohexitone et de propofol sont mesurées par analgésiométrie de compression sur la queue du rat et comparées avec des animaux de contrôle sous perfusion au soluté physiologique. Les seuils nociceptifs sont correlés avec les mesures de concentration plasmatique des drogues et par l’évaluation du comportement. La comparaison du seuil nociceptif avant la perfusion avec le seuil le plus bas obtenu pendant la perfusion révèle des diminutions dans tous les groupes de traitement. En pourcentage des valeurs de préinfusion, les diminutions sont les suivantes: thiopentone: 42,5% (P < 0.001), pentobarbitone: 27,8% (P = 0,014), méthohexitone: 24.9% (P = 0,013), propofol: 21,6% (P = 0,006). Il n’y a pas de changement dans les groupes contrôle au regard du seuil nociceptif. La relation entre le seuil nociceptif et la concentration plasmatique des drogues est ordinairement caractérisée par une baisse initiale suivie par une augmentation du seuil nociceptif à mesure que la concentration plasmatique et le niveau de sédation augmentent. Ces résultats supportent l’hypothèse selon laquelle l’hyperalgie serait une propriété de plusieurs anesthésiques quand ils sont administrés à des concentrations sous- hypnotiques.

Plasma, Brain, and Spinal Cord Concentrations of Thiopental Associated with Hyperalgesia in the Rat

BackgroundAlthough low doses of barbiturates are widely believed to increase sensitivity to pain, studies of the electrophysiologic effects of these drugs on the neurons involved in nociception in the spinal cord have detected only depressant effects. The goal of the studies reported here was to quantify the hyperalgesia resulting from low-dose thiopental infusions and to measure the associated concentrations of thiopental in the plasma, brain, and spinal cord. MethodsNociception was measured using the threshold for motor response to pressure stimulation of the tail (nociceptive threshold) and tail flick latency in the rat. Thiopental was administered by intravenous infusions designed to produce plasma concentrations that either slowly increased or remained at a steady state. Plasma and tissue thiopental concentrations were measured by high-performance liquid chromatography. ResultsWe observed a reduction in nociceptive threshold that was correlated with the plasma thiopental concentration over the range 2–20 μg.ml−1 (7.6–76 μM). The relationship was nonlinear. Nociceptive threshold reached a nadir (36% less than control values) at a mean plasma thiopental concentration of 13.7 μg.ml−1 (51.9 μM). The steady-state study showed a similar reduction in nociceptive threshold, with an equilibrium plasma thiopental concentration of 7.6 ± 1.3 μg.ml−1 (28.8 ± 4.9 μM). Concentrations of thiopental in brain and spinal cord samples were 1.7 ± 0.03 and 3.5 ± 1.7 μg.g−1, respectively. ConclusionsThese studies confirm previous reports of hyperalgesia in association with small doses of thiopental. Reductions in nociceptive threshold and tail flick latency were observed in association with spinal cord concentrations of thiopental in a range reported by others to depress the electrophysiologic activity of neurons involved in nociception.

Small-dose pentobarbital enhances synaptic transmission in rat hippocampus

We investigated the contribution of bicarbonate ion, &ggr;-aminobutyric acid-A (GABAA) receptors, and N-methyl-d-aspartate (NMDA) receptors to pentobarbital-induced enhancement of excitatory synaptic transmission in the hippocampal slice. Transverse hippocampal slices (400 &mgr;m thick) were prepared from 20- to 30-day-old Sprague-Dawley rats and maintained in an interface chamber perfused with warmed (35°C) oxygenated artificial cerebrospinal fluid. Extracellular field potentials, evoked by orthodromic paired-pulse stimulation of the Schaffer collateral CA1 pathway, were analyzed for the population spike (PS) amplitude. Pentobarbital had a concentration-dependent, biphasic effect on PS amplitudes, which were increased approximately twofold (P < 0.001) when the slice was exposed to pentobarbital concentrations of 1 and 5 &mgr;M and depressed at drug concentrations larger than 10 &mgr;M. Pentobarbital (5 &mgr;M) did not increase the PS amplitude when stimulation was stopped during exposure to the drug. The enhancement of PS amplitude was suppressed in the presence of 10 &mgr;M acetazolamide, a nonselective carbonic anhydrase inhibitor, and when the slice was bathed in CO2/HCO3−-free artificial cerebrospinal fluid. Pretreatment with 1 &mgr;M picrotoxin, a GABAA receptor antagonist, or 5 &mgr;M 2-amino-5-phosphopentanoic acid, a specific NMDA receptor antagonist, also suppressed enhancement of PS amplitude by 5 &mgr;M pentobarbital. The results suggest that small concentrations of pentobarbital (1 and 5 &mgr;M) enhance synaptic transmission through mechanisms involving GABAA and NMDA receptors and the HCO3− ion.

Levetiracetam Reduces Anesthetic-Induced Hyperalgesia in Rats

BACKGROUND:As part of an increase in excitability, small doses of pentobarbital, propofol, and midazolam induce an increased sensitivity to pain. Specific therapy to prevent or reduce this excitability may offer advantages over current clinical management with analgesics and sedatives. The pharmacological profile of the novel antiepileptic drug, levetiracetam, suggests that it may reduce the intensity of the excitatory stages of anesthesia. METHODS:We examined the influence of levetiracetam on the reduction of the nociceptive reflex threshold in rats by sedative doses of pentobarbital, propofol, and midazolam. Measurements of nociceptive reflex threshold to pressure and heat were made and then repeated after intraperitoneal injection of saline or one of three doses of levetiracetam (100, 200, 500 mg/kg). Pentobarbital (30 mg/kg), propofol (30 mg/kg), or midazolam (1.9 mg/kg) were then administered. The reflex threshold was measured every 10 min, starting at 5 min after the sedative injection, until 65 min had elapsed. RESULTS:Levetiracetam did not alter nociceptive reflex threshold in nonsedated animals (P = 0.11) or influence the degree or duration of sedation. The three anesthetic/sedative drugs reduced the nociceptive reflex threshold by 20%–30% of control values. Levetiracetam reduced the hyperreflexia associated with pentobarbital and midazolam (P < 0.05), but not propofol. CONCLUSIONS:These findings support further investigation into the role of levetiracetam in the prevention of anesthetic-induced excitability.

Nocifensive reflex thresholds in rats: measures of central nervous system effects of barbiturates

PurposeTo characterize the pharmacodynamic relationships between plasma pentobarbitone and thiopentone concentrations and nocifensive reflexes during emergence from anaesthesia.MethodsForty-nine rats were studied. Plasma barbiturate concentrations were measured with high performance liquid chromatography. Noofensive reflexes were assessed with the hindlimb withdrawal latency (WL) to heat and the somatic motor response threshold (SMRT) to tail pressure. In Protocol I, SMRT. WL. sedation, and the presence of paw-licking and the righting reflex were assessed in unrestrained rats before and every 10 min for two hours after an intrapentoneal injection of pentobarbitone (30 mg · kg−1). Plasma pentobarbitone kinetics were determined in a separate group of rats. In Protocol II. SMRT and drug concentrators were measured concurrently in partially restrained animals before and for 35 min after a computer-controlled iv bolus of thiopentone. In Protocol III the SMRT-plasma thiopentone relationship was determined during increasing and decreasing plasma thiopentone concentrations.ResultsEnhancement of both nocifensive reflexes was observed in the unrestrained animals. Enhancement of SMRT was maximal [175% (153–197) of control values] at a mean plasma thiopentone concentration of 11 (9–13) μg · ml−1. The SMRT-plasma thiopentone curve showed a mean efflux-influx difference in plasma thiopentone concentration of 4 (2.3–5.7) μg · ml−1.ConclusionBarbiturate-associated nocifensive reflex enhancement occurs in unrestrained animals with both thermal and pressure stimuli. The SMRT-plasma thiopentone concentraton relatonship during emergence from anaesthesia was similar to that observed previously during induction. The thiopentone plasma concentration-SMRT plot showed an equilibration delay similar to that previously described by others for thiopentone at an etectroencephalographic effect site.RésuméObjectifPréciser les relations pharmacodynamiques entre les concentrations de pentobarbitone et de thiopentone et les réflexes nocifs de défense pendant le réveil anesthésique.MéthodesQuarante-neuf rats ont été étudiés. Les concentrations plasmatiques de barbituriques ont été mesurées par Chromatographie liquide à haute performance. Les réflexes nocifs de défense ont été évalués par la latence du retrait (LR) du membre postérieur provoqué par la chaleur et par te seuil de réponse motrice somatique (SRMS) au serrement de la queue. Dans te protocote I. le SRMS, la LR. le degré de sédation et l’existence du léchage de la patte et du réflexe de redressement ont été recherchés sur des rats sans contention avant et aux dix min pendant deux heures après une injecton intrapéntoméale de pentobarbitone (30 mg · kg−1). La Cinétique plasmatique du pentobarbitone a été déterminée chez un groupe séparé de rats. Dans te protocole II. le SRMS et les concentrations de thiopentone ont été mesurés simultanément chez des rats sous contention partielle avant et 35 min après l’administration contrôlée par ordinateur d’un bolus de thiopentone. Dans te protocole III. la relation entre le SRMS et la concentration de thiopentone a été déterminée au moment de la croissance et la décroissance plasmatique du thiopentoneRésultatsOn a observé une facilitation des deux réflexes nocifs de défense chez les rats sans contenton. La facilitation du SRMS était maximale [ 175% (153 –197) des valeurs initiales] à la concentration plasmatique moyenne de thiopentone de II (9–13) μ · ml−1. La courbe SRMS/thiopentone a révélé une différence efflux-influx de la concentration plasmatique de thiopentone de 4 (2.3–5.7) g · ml−1.ConclusionUne facilitation du réflexe nocif de défense associée aux barbituriques suivent chez des rats sans con tenton stimulés par la chaleur ou la compresson. La relaton entre te SRMS et la concentraton plasmatique du thiopentone pendant te réveil anesthésique est identique à celte qui a déjà été observée à l’induction. Le graphique concentraton-SRMS montre un délai d’équilibraton identique a celui déjà décnt par d’autres pour te thiopentone au niveau d’un site effecteur électroencéphalographique.

Spinal Carbonic Anhydrase Contributes to Nociceptive Reflex Enhancement by Midazolam, Pentobarbital, and Propofol

Background Systemic administration of acetazolamide blocks nociceptive hyperreflexia induced by pentobarbital. The authors assessed the effect of intrathecal carbonic anhydrase inhibitors (CAIs) on nociceptive reflex enhancement by pentobarbital, propofol, and midazolam. Methods Twenty-seven rats with chronic indwelling subarachnoid catheters were studied. Nociceptive paw reflex latency (PWL) for paw withdrawal from radiant heat was measured in forelimbs and hind limbs. Measurements were obtained under control conditions, 15 min after lumbar intrathecal injection of 10 &mgr;l artificial cerebrospinal fluid containing the CAIs acetazolamide or ethoxyzolamide, and during the 55 min after intraperitoneal injection of three sedative drugs: 30 mg/kg pentobarbital, 50 mg/kg propofol, or 1.9 mg/kg midazolam. Results Control values of PWL averaged 10.9 ± 1.5 s in the forelimbs and 11.1 ± 1.6 s in the hind limbs (P = 0.18). Intrathecal injection of 50 &mgr;m ethoxyzolamide reduced PWL by 8% and 4% in the forelimbs and hind limbs, respectively (P = 0.01); all other CAI injections had no effect on PWL. Following anesthetic injection, PWL in the forelimbs was reduced by approximately 35–40% of control values; in the hind limbs, CAI treatment decreased the PWL reduction to 8–16% for pentobarbital (P < 0.001), 30–32% for propofol (P < 0.02), and 9–16% for midazolam (P < 0.001). The hind limb reduction of hyperreflexia by CAI was less for propofol than for midazolam or pentobarbital (P < 0.002). Conclusion Spinal carbonic anhydrase contributes to nociceptive hyperreflexia induced by pentobarbital and midazolam and to a lesser extent with propofol. These findings are consistent with a role for carbonic anhydrase in nociceptive signal enhancement by these drugs.

Pentobarbital induces nocifensive hyperrflexia, not hyperalgesia in rats

Purpose: To seek behavioural, reflexive and histochemical evidence of long-lasting changes in nociceptive stimulus transmission induced by exposure to doses of pentobarbital that induce nocifensive hyperreflexia.Methods: Nocifensive hyperreflexia was induced in 12 rats with 30 mg·kg−1 pentobarbitalip. Reflex latency times for withdrawal of the hind paw from noxious radiant heat were measured with an automated electronic timer. Subjective responses to noxious stimulation (licking or biting of the stimulated hindpaw) and the level of sedation were recorded. Histological sections of lumbar spinal cord were stained for immunoreactivity of the immediate-early-gene (IEG0, c-fos, in three rats that repeated threshold noxious radiant heat stimulation during the period of nocifensive hyperreflexia induced by 30 mg·kg−1 pentobarbitalip.Results: Reflex withdrawal latency decreased by 32±8% of control values (P<0.001) following pentobarbital injection and returned to control values 120 min after drug injection. Once fully alert, pentobarbital-treated animals did not show any increase in nociceptive behaviour relative to saline-injected controls (P=0.41). Sustained noxious stimulation to the hindpaw in halothane-anesthetized animals was associated with an increase inc-fos immunoreactivity in the dorsal horn of the lumbar spinal cord ipsilateral to the stimulation (P<0.001). Threshold stimulation in the pentobarbital-treated animals was not associated with any increase inc-fos expression.Conclusions: During pentobarbital-induced hyperreflexia, rats did not show any reflexive, behavioural, or histochemical evidence of long-lasting enhancement of nocifensive signal transmission. The results are consistent with previous observations that, in the absence of tissue injury, nocifensive hyperreflexia induced by barbiturates is a short-lived pharmacological effect.RésuméOjectif: Découvrir les manifestations comportementales, réflexes et histochimiques de modifications persistantes de la transmission d’un stimulus nociceptif induit par l’exposition à des doses de pentobarbital qui provoquent une surréflectivité défensive.Méthode: La surréflectivité défensive a été induite chez 12 rats avec 30 mg·kg−1 de pentobarbitalip. Les temps de latence réflexe nécessaire au retrait de la patte arrière d’une source de chaleur radiante ont été mesurés avec un chronomètre électronique automatisé. Les réponses subjectives à la stimulation désagréable (lécher ou mordre la patte stimulée) et le niveau de sédation ont été enregistrés. Des sections histologiques de la moelle épinière lombaire ont été colorées pour vérifier l’immunoréactivité du gène précoce une stimulation liminale novice répétée de chaleur radiante pendant la période de surréflectivité défensive induite par les 30 mg·kg−1 de pentobarbitalip.Résultats: Le temps de latence réflexe a baissé de 32±8 % par rapport aux valeurs témoins (P<0,001) après l’injection de pentobarbital et est revenu aux valeurs témoins 120 min après l’injection du médicament. Une fois complètement réveillés, les animaux traités au pentobarbital n’ont pas affiché de comportement nociceptif accru comparés aux animaux témonis à qui on a injecté une solution salée (P=0,41). La stimulation nocive à la patte arrière, subie par les animaux anesthésiés à l’halothane, a été associée avec un accroissement de l’immunoréactivité au gènec-fos dans la corne supérieure de la moelle épinière lombaire homolatérale à la stimulation (P<0,001). La stimulation liminale chez les animaux traités au pentobarbital n’était pas accompagnée d’une augmentation de l7rsexpression dec-fos.Conclusion: Pendant la surréflectivité liée au pentobarbital, les rats n’ont pas donné de signe réflexe, comportemental ou histochimique d’une augmentation persistante de la transmission du signal défensif. Ces résultats confirment des observations antérieures qui montraient qu’en l’absence de l’sion aux tissus la surréflectivité défensive induite par les barbituriques présente un effet pharmacologique de courte durée.

Thiopentone induced enhancement of somatic motor responses to noxious stimulation : influence of GABAA receptor modulation

PurposeThis study was conducted to determine whether hyperalgesic effects of subanaesthetic concentrations of thiopentone could be attributed to GABAA receptor effects.MethodsAll studies were performed on 50 rats in a prospective, randomized, blinded fashion using saline-injected animals as controls. Using a modified Randall-Selitto technique, the motor behavior stimulated by noxious stimulation was quantified by determining the lowest tail pressure required to provoke a withdrawal response (somatic motor response threshold, SMRT). In the first protocol (21 rats), we studied the effects of 0.5, 1.5 and 5 mg · kg−1 iv of the GABAA agonist, muscimol, on SMRT. In the second protocol (20 rats), the effects of administration of saline, muscimol 0.5 mg · kg−1, or the competitive GABAA antagonist, bicuculline 0.25 mg · kg−1, upon the SMRT-reducing effects of a standardized thiopentone infusion were observed.ResultsNo dose of muscimol produced hyperalgesia. The highest dose of muscimol used (5 mg · kg−1) produced pronounced analgesic effects, raising the SMRT above 750 g. No change in SMRT was detected with the smaller doses of muscimol. Given in combination with muscimol (0.5 mg · kg−1), thiopentone produced analgesia, as shown by an increase in SMRT (P = 0.009). In the bicuculline treated animals, SMRT decreased linearly with increasing plasma thiopentone concentrations (P < 0.001). The slope of the relationship in the bicuculine group was not significantly different from that observed in the saline-treated group, indicating that bicuculline did not block the hyperalgesic effects of thiopentone.ConclusionThe results of these studies suggest that hyperalgesia associated with thiopentone is not mediated primarily by GABAA receptors.RésuméObjectifCette étude visait à déterminer si les effets hyperalgiques produits par des concentrations sous-anesthésiques de thiopentone peuvaient être attribués à la médiation des récepteurs GABAA.MéthodesToutes tes expériences ont été réalisées de façon aléatoire, prospective et en double aveugle sur 50 rats avec des contrôles au soluté physiologique. A l’aide d’une technique modifiée de Randall-Selitto, le comportement moteur après stimulation nocive a été quantifié en déterminant la pression la plus basse requise pour provoquer le retrait de la queue (le seuil de réponse motrice somatique, SRMS). Dans un premier protocole (21 rats), les effets sur le SRMS de 0,5, 1,5 et 5 mg · kg−1 iv d’un antagoniste GABAA, le muscimol ont été étudiés. Dans un deuxième protocole (20 rats), on a observé les effets de l’administration de sol. phys., de muscimol 0,5 mg · kg−1 ou de l’antagoniste compétitif du GABAA la bicuculline 0,25 mg · kg−1.RésultatsAucune des doses de muscimol n’a provoqué d’hyperalgie. La dose la plus forte de muscimol (5 mg · kg−1) a produit un effet analgésique prononcé, élevant le SRMS au-dessus de 750 g. On n’a pas décelé de changement de SRMS avec doses plus faibles de muscimol. Administré en association au muscimol (0,5 mg · kg−1), le thiopentone produit de l’analgésie, comme le montre l’augmentation du SRMS (P = 0,009). Chez les animaux traités, à la bicuculline, le SRMS a diminué de façon linéaire avec l’augmentation des concentrations plasmatiques de thiopentone (P < 0,001). Dans le groupe bicuculline, la pente de la relation n’était pas différente de celle observée dans le groupe traité au sot. phys., démontrant ainsi que la bicuculline ne bloque pas les effets hyperalgiques du thiopentone.ConclusionLes résultais de ces études suggèrent que l’hyperalgie associée au thiopentone ne se produit pas principalement par la médiation des récepteurs GABAA.

The Influence of Cryogenic Brain Injury on the Pharmacodynamics of Pentobarbital Evidence for a Serotonergic Mechanism

To study of the influence of brain injury on the pharmacodynamics of pentobarbital, the authors examined the effect of a focal cortical freezing lesion in rats on the brain concentration of pentobarbital associated with lack of response to tail clamp. The freezing lesion was made with a probe (-50 degrees C) applied through a craniotomy to the intact dura over the left parietal cortex. Three days after injury the rats were anesthetized with a continuous intravenous infusion of pentobarbital until they first did not respond to tail clamp stimulation. The brains were then removed for determination of pentobarbital by high-performance liquid chromatography. The brain pentobarbital concentration required to prevent response to tail clamp (EC50) was reduced from 209 +/- 39 nmol/g (mean +/- standard deviation) in rats without brain injury to 149 +/- 28 nmol/g in the injured animals (P = 0.005). The cortical serotonin (5-HT) concentration was increased from 1904 +/- 358 pmol/g in uninjured rats to 2513 +/- 598 pmol/g (P less than 0.01) in injured animals ipsilateral to the lesion. Pretreatment of the rats with p-chlorophenylalanine (PCPA, 200 mg/kg by intraperitoneal injection) to inhibit 5-HT synthesis abolished both the increase in 5-HT concentration associated with the injury (left cortex, 708 +/- 389 pmol/g; right cortex, 911 +/- 979 pmol/g) and the effect of the lesion on EC50 (uninjured, EC50 = 186 +/- 24 nmol/g; injured, EC50 = 179 +/- 47 nmol/g). Prevention of the decrease in EC50 by inhibition of 5-HT synthesis provides support for a functional role for 5-HT in the influence of cold injury on the pharmacodynamics of pentobarbital.

The influence of cryogenic brain injury on nociception in the rat.

Background:Previous studies have suggested that focal cryogenic brain lesions that cause functional cerebral depression may increase anesthetic potency. To determine whether this effect was caused by changes in nociception, this study prospectively evaluated the influence of an experimental focal brain injury on the analgesic effects of the opioids, fentanyl and alfentanil, in rats. Methods:The cortical freezing lesion was made with a brass probe cooled to −50° C, applied through a craniotomy to the intact dura for 5 s. The analgesic effects of the opioids were quantified by tail-flick latency 3 days after the injury. The prolongation of tail-flick latency by infusions of each opioid in animals injured with a standardized cortical freezing lesion was compared with the results obtained from sham-operated control animals. Results:At the endpoint of the experiment, prolongation of the tail-flick latency to 10 s, the mean serum concentrations (EC50) of both fentanyl and alfentanil were approximately 25% less in the brain-injured animals than in the controls (EC50 fentanyl; injured: 10.2± 2.6 ng/ml, controls: 13.6 ± 5.2 ng/ml [P < 0.02]; EC50 alfentanil; injured: 54.7 ±9.2 ng/ml, controls: 74.3 ±18.4 ng/ml [P< 0.02]). For alfentanil, no significant differences in pharmacokinetics between injured and control animals were observed. Conclusions:These results support the hypothesis that reductions in anesthetic requirements in this animal model of brain injury may be caused, in part, by alterations in nociception.