Methods: Sprague–Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and for their paw flinches by formalin injection after intrathecal administration of AP-5 or YM 872. The effects of the combination were tested by an isobolographic analysis using 50% effective dose (ED50). Total fractional dose was calculated as (ED50 dose of AP-5 in combination)/(ED50 dose of AP-5 alone)+(ED50 dose of YM 872 in combination)/(ED50 dose of YM 872 alone).
Results: Intrathecally administered AP-5, YM 872, and their combination produced dose-dependent increases of the tail-flick latency and decreases in the number of flinches in both phase 1 and 2 of the formalin test. The ED50 values of the combination were significantly lower than the calculated additive values ( P <0.01). Total fractional dose value was 0.22 in the tail flick test, 0.12 in the phase 1 and 0.14 in the phase 2 of the formalin test.
Conclusion: An NMDA receptor antagonist, AP-5 and an AMPA receptor antagonist, YM 872 had synergistic antinociceptive effects on both acute thermal and inflammatory induced acute and facilitated nociception. 相似文献
Methods: Rats were given a 3- or 4-week course of twice daily administration of desipramine, 10 mg/kg, or saline. The effect of a hypnotic dose of dexmedetomidine, 250 [micro sign]g/kg given intraperitoneally, on the duration of loss of righting reflex was determined. The tail flick latency response was determined before and after 50 [micro sign]g/kg dexmedetomidine. The minimum anesthetic concentration of halothane and the central norepinephrine turnover rate were determined before and after administration of 30 [micro sign]g/kg dexmedetomidine. Changes in the affinity and density of the [Greek small letter alpha]2-adrenergic receptor in locus coeruleus and spinal cord also were determined.
Results: Treatment with desipramine decreased dexmedetomidine-induced loss of righting reflex duration by 67% and eliminated the antinociceptive effect of dexmedetomidine. Dexmedetomidine produced a 55% decrease in minimum anesthetic concentration in the control group but no reduction in desipramine-treated rats. Desipramine did not change the receptor density or binding affinity of [Greek small letter alpha]2 receptors at the site for hypnotic (locus coeruleus) or antinociceptive (spinal cord) responses. No decrement in the central norepinephrine turnover rate was noted in the locus coeruleus of dexmedetomidine after 3 weeks of treatment with desipramine. The [Greek small letter alpha]1-adrenergic antagonist prazosin at 1 or 5 mg/kg completely (minimum anesthetic concentration reduction), almost completely (antinociceptive), or partially (hypnotic) restored responsiveness to normal. 相似文献
Methods: Sprague-Dawley rats (weight, 250-300 g) were implanted with chronic lumbar intrathecal catheters and were assigned to receive one of several doses of morphine-ACEA 1021 (NMDA glycine site antagonist), ACEA 2085 (AMPA antagonist), AP-5 (NMDA antagonist), saline or vehicle-and were tested for their effect on the response latency using a 52.5 [degree sign]C hot plate. The combinations of morphine and other agents also were tested.
Results: Intrathecal morphine (ED50:2 [micro sign]g/95% confidence interval, 1-4 [micro sign]g) and ACEA 2085 (6 ng/2-15 ng), but not AP-5 or ACEA 1021, yielded a dose-dependent increase in the thermal escape latency. A systematic isobolographic analysis was carried out between intrathecal morphine and ACEA 2085 using the ED50 dose ratio of 357:1. A potent synergy was observed with decreased side effects. Morphine dose- response curves were carried out for morphine and fixed doses of ACEA 1021 (12 [micro sign]g) or AP-5 (10 [micro sign]g). No synergistic interactions were noted. 相似文献
Methods: CHO-[micro sign], CHO-[small kappa, Greek], and CHO-[small delta, Greek] membranes were incubated with the opioid receptor radioligand [(3) H] diprenorphine at room temperature. Ketamine (racemic, R(-) and S(+)) was included at concentrations covering the clinical range. CHOORL1 membranes were incubated with [(125) I]Tyr14 nociceptin and racemic ketamine at room temperature. The effects of racemic ketamine and selective opioid receptor agonists ([micro sign] [D-Ala2, MePhe4, Gly(ol)5] enkephalin (DAMGO); [Greek small letter kappa spiradoline or [small delta, Greek]: [D-pen2, D-pen5] enkephalin (DPDPE)) on forskolin-stimulated cyclic adenosine monophosphate formation also were examined. Data are mean +/- SEM.
Results: Racemic ketamine increased the radioligand equilibrium dissociation constant for [(3) H]diprenorphine from 85 +/- 5 to 273 +/- 11, 91 +/- 6 to 154 +/- 16, and 372 +/- 15 to 855 +/- 42 pM in CHO-[micro sign], CHO-[small kappa, Greek], AND CHO-[small delta, Greek], respectively, The concentration of radioligand bound at saturation was unaffected. In CHO-[micro sign] and CHO-[small kappa, Greek], cells, racemic, ketamine did not slow the rate of naloxone-induced [(3) H]diprenorphine dissociation. Ketamine and its isomers also displaced [(3) H]diprenorphine binding to [micro sign], [small kappa, Greek], and [small delta, Greek] receptors in a dose-dependent manner, with pKi values for racemic ketamine of 4.38 +/- 0.02, 4.55 +/- 0.04, and 3.57 +/- 0.02, respectively. S(+)-ketamine was two to three times more potent than R(-)-ketamine at [micro sign] and [small kappa, Greek] receptors. Racemic ketamine displaced [(125) I]Tyr14 nociceptin with an estimated affinity constant of 0.5 mM. Racemic ketamine inhibited the formation of cyclic adenosine monophosphate (naloxone insensitive) in a dose-dependent manner (concentration producing 50% inhibition [tilde operator] 2 mm) in all cell lines, including untransfected CHO cells. Ketamine (100 [micro sign]M) reversed DAMGO ([micro sign]) and spiradoline ([small kappa, Greek]) inhibition of formation of cyclic adenosine monophosphate. 相似文献
Methods: Purified synaptosomes were preloaded with [(3) H]GABA and superfused with buffer containing aminooxyacetic acid and nipecotic acid to inhibit GABA metabolism and reuptake, respectively. Spontaneous and elevated potassium chloride depolarization-evoked [(3) H]GABA release were evaluated in the superfusate in the absence or presence of various anesthetics, extracellular Ca2+, GABA receptor agonists and antagonists, and 2,4-diaminobutyric acid.
Results: Propofol, etomidate, pentobarbital, and alphaxalone, but not ketamine, potentiated potassium chloride-evoked [(3) H]GABA release (by 1.3 to 2.9 times) in a concentration-dependent manner, with median effective concentration values of 5.4 +/- 2.8 [micro sign]M (mean +/- SEM), 10.1 +/- 2.1 [micro sign]M, 18.8 +/- 5.8 [micro sign]M, and 4.4 +/- 2.0 [micro sign]M. Propofol also increased spontaneous [(3) H]GABA release by 1.7 times (median effective concentration = 7.1 +/- 3.4 [micro sign]M). Propofol facilitation of [(3) H]GABA release was Ca2+ dependent and inhibited by bicuculline and picrotoxin, but was insensitive to pretreatment with 2,4-diaminobutyric acid, which depletes cytoplasmic GABA pools. 相似文献
Methods: The authors evaluated the interactions between propofol and midazolam in modulating GABAA receptor activity in embryonic hippocampal neurons. The effects of midazolam and propofol on peak current evoked by submaximal concentrations of GABA were studied using the patch clamp method. Isobolographic analysis was undertaken by constructing concentration-response curves for midazolam and propofol alone and then evaluating the potency of combinations of midazolam and propofol. In other experiments, the concentration of GABA was increased and flurazepam was substituted for midazolam.
Results: Isobolographic analysis confirmed that midazolam and propofol interact synergistically to enhance currents evoked by low concentrations of GABA (1 [micro sign]M). However, when the concentration of GABA was increased to 3 [micro sign]M, the interaction was additive. The interaction between flurazepam and propofol was also additive for enhancement of currents evoked by 3 [micro sign]M GABA. 相似文献
Methods: Rats received a continuous intrathecal infusion of morphine (0.3-10 [micro sign]g [middle dot] kg-1 [middle dot] h-1), lidocaine (30-1000 [micro sign]g [middle dot] kg-1 [middle dot] h-1), a combination of those, or saline. After 6- day infusion, intrathecal morphine challenge test (5 [micro sign]g/10 [micro sign]l) was performed, and time-response curve was constructed to assess the magnitude of tolerance. The tail flick (TF) test and colorectal distension (CD) test were used to measure somatic and visceral antinociceptive effects, respectively.
Results: Antinociceptive effects in the TF and CD tests caused by morphine challenge were reduced (P < 0.01) in the morphine infused groups. The magnitude of the tolerance was inversely associated with the amount of morphine infused. Lidocaine infusion induced no different change in the morphine challenge test from that seen in the saline infusion group. Development of tolerance was greater in morphine 3 [micro sign]g [middle dot] kg-1 [middle dot] h-1 than in morphine 0.75 [micro sign]g [middle dot] kg-1 [middle dot] h-1 + lidocaine 150 [micro sign]g [middle dot] kg-1 [middle dot] h-1 despite their similar antinociceptive effects during intrathecal infusion. The infusion of a low dose of morphine (0.3 [micro sign]g [middle dot] kg-1 [middle dot] h-1) did not reduce the antinociceptive effects in the challenge test. 相似文献
Method: The authors measured whole-cell currents in the rat cultured cortical neuron at holding potential of -60 mV. Kainate 500 [micro sign]M was applied as the agonist for AMPA receptors. Thiopental (3-300 [micro sign]M), R(-)-MPPB or S(+)-MPPB (100-1,000 [micro sign]M) was coapplied with kainate under the condition in which the GABAA receptor-mediated current was blocked. Effects of MPPB isomers on the current elicited by GABA 1 [micro sign]M were studied in the separate experiments.
Results: Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 [micro sign]M. Both R(-)-MPPB and S(+)-MPPB inhibited the kainate-induced current with a little stereoselectivity. R(-)-MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)-MPPB enhanced but S(+)-MPPB reduced the GABA-induced current. 相似文献
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. 相似文献
Methods: After Institutional Review Board approval and informed consent, 48 patients (n = 12) undergoing knee surgery were randomly allocated to one of four groups and studied in a prospective way. After 0.05-0.1 mg/kg intravenous midazolam premedication, patients were randomized to receive 20 mg intrathecal bupivacaine plus epidural lidocaine (85 mg) with saline (control group); 1 [micro sign]g/kg epidural neostigmine (1 [micro sign]g group); 2 [micro sign]g kg epidural neostigmine (2 [micro sign]g group); or 4 [micro sign]g/kg epidural neostigmine (4 [micro sign]g group). The concept of the visual analog scale, which consisted of a 10-cm line with 0 equaling "no pain at all" and 10 equaling "the worst possible pain" was introduced. Post-operatively, pain was assessed using the visual analog scale, and intramuscular 75 mg diclofenac was available at patient request.
Results: Groups were demographically the same and did not differ in intraoperative characteristics (blood pressure, heart rate, ephedrine consumption, oxyhemoglobin saturation, sensory loss before start of surgery, or duration of sensory motor block). The visual analog scale score at first rescue analgesic and the incidence of adverse effects were similar among groups (P > 0.05). The time (min +/- SD) to first rescue analgesic was as follows: control group: 205 +/- 48; 1-[micro sign]g group: 529 +/- 314; 2-[micro sign]g group: 504 +/- 284; 4-[micro sign]g group: 547 +/- 263 (P < 0.05). The analgesic consumption (number of intramuscular diclofenac injections [mean, 25th-75th percentile]) in 24 h was as follows: control group: 3 [3 or 4]; 1-[micro sign]g group: 1[1 or 2]; 2-[micro sign]g group: 2[1 or 2]; 4-[micro sign]g group: 2[1-3](P < 0.05). The 24-h-pain visual analog scale score (cm +/- SD) that represents the overall impression for the last 24 h was as follows: control group: 5 +/- 1.6; 1-[micro sign]g group: 1.6 +/- 1.8; 2-[micro sign]g group: 1.4 +/- 1.6; 4-[micro sign]g group: 2.2 +/- 1.9 (P < 0.005). The incidence of adverse effects was similar among groups (P > 0.05). 相似文献
Methods: Wild-type mouse muscle nicotinic receptors and receptors containing pore mutations ([Greek small leter alpha] S252I + [Greek small letter beta] T263I) were studied electrophysiologically in membrane patches from Xenopus oocytes. Patch currents evoked by brief pulses of acetylcholine were measured in the presence of enflurane and two nonanesthetics, 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane. Nonanesthetic interactions with human serum album were assessed by quenching of intrinsic protein fluorescence.
Results: Both anesthetic and nonanesthetic volatile compounds inhibited wild-type and [Greek small letter alpha] S252I + [Greek small letter beta] T263I mutant nicotinic channels but displayed different selectivity for open versus resting receptor states. Median inhibitory concentrations (IC50 s) in wild-type nicotinic receptors were 870 +/- 20 [micro sign]M for enflurane, 37 +/- 3 [micro sign]M for 1,2-dichlorohexafluorocylcobutane, and 11.3 +/- 5.6 [micro sign]M for 2,3-dichlorooctafluorobutane. For all three drugs, ratios of wild-type IC50 s to mutant IC50mut ranged from 7-10, and ratios of wild-type IC50 s to predicted anesthetic median effective concentrations (EC50 s) ranged from 1.8-2.3. 1,2-Dichlorohexafluorocyclobutane quenched human serum albumin with an apparent dissociation constant (Kd) of 160 +/- 11 [micro sign]M. The ratios of dissociation constants to predicted EC50 s for the nonanesthetics were within a factor of two of the dissociation constant:EC (50) ratios calculated for halothane and chloroform from previous published results. 相似文献
Methods: The study consisted of two parts. In an open dose-finding study (part 1), the intravenous dose of atipamezole to reverse the sedative effects of 2.5 [micro sign]g/kg of dexmedetomidine given intramuscularly was determined (n = 6). Part 2 was a placebo-controlled, double-blinded, randomized cross-over study in which three doses of atipamezole (15, 50, and 150 [micro sign]g/kg given intravenously in 2 min) or saline were administered 1 h after dexmedetomidine at 1-week intervals (n = 8). Subjective vigilance and anxiety, psychomotor performance, hemodynamics, and saliva secretion were determined, and plasma catecholamines and serum drug concentrations were measured for 7 h.
Results: The mean +/- SD atipamezole dose needed in part 1 was 104 +/- 44 [micro sign]g/kg. In part 2, dexmedetomidine induced clear impairments of vigilance and psychomotor performance that were dose dependently reversed by atipamezole (P < 0.001). Complete resolution of sedation was evident after the highest (150 [micro sign]g/kg) dose, and the degree of vigilance remained high for 7 h. Atipamezole dose dependently reversed the reductions in blood pressure (P < 0.001) and heart rate (P = 0.009). Changes in saliva secretion and plasma catecholamines were similarly biphasic (i.e., they decreased after dexmedetomidine followed by dose-dependent restoration after atipamezole). Plasma norepinephrine levels were, however, increased considerably after the 150 [micro sign]g/kg dose of atipamezole. The pharmacokinetics of atipamezole were linear, and elimination half-lives for both drugs were approximately 2 h. Atipamezole did not affect the disposition of dexmedetomidine. One person had symptomatic sinus arrest, and another had transient bradycardia approximately 3 h after receiving dexmedetomidine. 相似文献
Methods: Behavioral responses to heat and mechanical and chemical stimuli were studied in NK-1 receptor knockout mice and wild-type control mice. Thermal nociception was evaluated by measuring paw lick or jump latencies to hot plate (52, 55, and 58[degree sign]C) and paw withdrawal latencies to radiant heat applied to the hind paws. Mechanical nociception was measured by von Frey monofilament applications to the hind paws. Intraplantar capsaicin-induced (10 [micro sign]g/20 [micro sign]l) paw licking and mechanical and heat hyperalgesia were compared in NK-1 knockout and wild-type mice.
Results: Withdrawal responses to radiant heat (4.3 +/- 0.18 s for knockout and 4.4 +/- 0.8 s for wild-type mice) and von Frey monofilaments were similar in knockout and wild-type mice. In the hot plate test, increasing the hot plate temperature from 52[degree sign]C to 58[degree sign]C resulted in a decrease in the response latency in the wild-type mice (30.4 +/- 17.5 s to 15.2 +/- 6.8 s, P < 0.05), whereas in the knockout mice the response latencies remained constant (28.2 +/- 19.8 s to 29 +/- 15.1 s, not significant). Capsaicin-induced paw licking (14.5 +/- 12.8 s for knockout and 41.3 +/- 37.3 s for wild-type mice, P < 0.05) and mechanical and heat hyperalgesia were attenuated in the knockout mice. 相似文献