Methods: Amitriptyline, morphine, or the combination of amitriptyline and morphine was administered systemically to rats, and antinociceptive effects were determined by means of the rat orofacial formalin test. Isobolographic analysis was used to define the nature of the interactions between morphine and amitriptyline.
Results: Amitriptyline as well as morphine produced a dose-related inhibition in the first phase and the second phase of rubbing activity. ED50 values against rubbing behavior were 14.6 mg/kg (95% confidence interval, 10.2-33.5 mg/kg) and 1.3 mg/kg (95% confidence interval, 1.0-1.7 mg/kg) for amitriptyline and morphine, respectively. Combinations of increasing fractional increments of amitriptyline and morphine ED50 doses produced a synergistic effect against rubbing behavior, as revealed by isobolographic analysis. 相似文献
Methods: Intrathecal catheters were implanted into male Wistar rats. Three days later, the acute nociceptive sensitivity was assessed using the tail-flick test. Analgesic latencies were converted to the percentage maximum possible effect. The dose that yielded 50% of the maximum possible effect (ED50) and dose-response and time-course curves were determined for the ketamines (30-300 [mu]g), morphine (0.1-3.0 [mu]g), dexmedetomidine (0.3-10.0 [mu]g), and mixtures of two doses of ketamines (30 or 100 [mu]g) with different doses of morphine or dexmedetomidine for fixed-dose analysis.
Results: Neither racemic ketamine nor its enantiomers alone had a significant effect on the tail-flick test, with the exception of the highest dose of racemic ketamine, which caused motor impairment. Morphine and dexmedetomidine each produced dose-dependent antinociception, with ED50 of 1.7 [mu]g (95% confidence interval: 1.04-2.32) and 4.85 [mu]g (3.96-5.79), respectively. A low dose (30 [mu]g) of racemic ketamine or its enantiomers did not influence the ED50 of morphine significantly. Coadministration of 100 [mu]g racemic ketamine or S (+)-ketamine, but not R (-)-ketamine, significantly enhanced and prolonged the antinociceptive effect of morphine. Both doses of racemic ketamine or its isomers significantly decreased the ED50 value for dexmedetomidine, although the higher dose of racemic or S (+)-ketamine had the highest potency. One-hundred micrograms of racemic ketamine or S (+)-ketamine also prolonged the effects of dexmedetomidine. 相似文献
Methods: First, rats were injected once with carrageenan in a hind paw, with fentanyl (60 or 100 [mu]g/kg each given four times at 15-min intervals [4 x 60 or 4 x100]) or saline. Second, rats were injected with carrageenan twice without fentanyl (7-day interval), with the second injection either in the previously injected paw or in the other paw. Third, rats were injected twice with carrageenan in the same hind paw: the first ketamine injection was given (10 mg/kg each given three times at 5-h intervals) with or without fentanyl (4 x 60 [mu]g/kg), and second injection was given without ketamine or fentanyl. The consequences of treatments on long-term hyperalgesia were examined by the paw-pressure vocalization test.
Results: The long-lasting hyperalgesia induced by the first carrageenan injection was dose-dependently enhanced in both duration and magnitude in 4 x 60 or 4 x 100 [mu]g/kg fentanyl-treated rats: 5 or 10 days, respectively, as compared with 2 days in saline-treated rats. Hyperalgesia observed in the hind paw contralateral to the first carrageenan injection was enhanced in fentanyl-treated rats. The second carrageenan injection, performed in any hind paw, induced an exaggerated hyperalgesia, especially in fentanyl-treated rats. Pretreatment with ketamine totally prevented the carrageenan- and fentanyl-induced enhancement of the long-lasting hyperalgesia. 相似文献
Methods: A total of 60 patients undergoing gynecologic surgery were randomized to one of five groups. Patients received 15 mg bupivacaine plus 2 ml of the test drug intrathecally (saline, 100 [mu]g morphine, or 1-5 [mu]g neostigmine). The control group received spinal saline as the test drug. The morphine group received spinal morphine as test drug. The morphine + 1 [mu]g neostigmine group received spinal morphine and 1 [mu]g neostigmine. The morphine + 2.5 [mu]g neostigmine group received spinal morphine and 2.5 [mu]g neostigmine. Finally, the morphine + 5 [mu]g neostigmine group received spinal morphine and 5 [mu]g neostigmine.
Results: The groups were demographically similar. The time to first rescue analgesic (minutes) was longer for all patients who received intrathecal morphine combined with 1-5 [mu]g neostigmine (median, 6 h) compared with the control group (median, 3 h) (P < 0.02). The morphine group (P < 0.05) and the groups that received the combination of 100 [mu]g intrathecal morphine combined with neostigmine (P < 0.005) required less rescue analgesics in 24 h compared with the control group. The incidence of perioperative adverse effects was similar among groups (P > 0.05). 相似文献
Methods : Male Wistar rats were implanted with intrathecal catheters that were advanced cephalad through a lumbar guide cannula to the high cervical spinal cord. The orofacial formalin test was used to assess antinociception. Vehicle or morphine (1, 3, 6, 10, 30 [mu]g) was injected intrathecally followed 10 minutes later by injection of formalin solution, 2.5%, into the vibrissal pad. Motor assessment and hemodynamic and respiratory blood gas measurements were evaluated in a separate group of animals.
Results : Intrathecal morphine produced a dose-dependent decrease in the first and second phases of the behavioral response (P < 0.05). The ED50 (95% confidence limits) values for the first and second phases were 6.65 [mu]g (3.52-14.9 [mu]g) and 3.40 [mu]g (2.37-4.61 [mu]g), respectively. Ten micrograms intrathecal naloxone antagonized the morphine effect (P < 0.05). Significant cardiovascular and respiratory depression was observed. No significant motor dysfunction was observed. 相似文献
Methods: During halothane anesthesia, a hind paw plantar incision was performed in rats receiving four fentanyl subcutaneous injections (100 [mu]g/kg per injection, every 15 min). In some groups, three subcutaneous ketamine injections (10 mg/kg per injection, every 5 h) were performed in saline- or fentanyl-treated rats. One day after surgery, the analgesic effect of morphine (2 mg/kg subcutaneous) was tested. Analgesia, mechanical hyperalgesia, tactile allodynia, and pain score were assessed for several days using the paw pressure vocalization test, the von Frey application test, and the postural disequilibrium test.
Results: Fentanyl induced analgesia but also produced exaggerated postoperative pain as indicated by the enhancement of hyperalgesia, allodynia, and weight-bearing decrease after hind paw plantar incision. Ketamine pretreatment prevented such a fentanyl-induced enhancement of postoperative pain and improved its management by morphine. 相似文献
Methods: Eight adult rhesus monkeys were used. Scratching responses were videotaped and counted by observers who were blinded to experimental conditions. Antinociception was measured by a warm-water (50[degrees]C) tail-withdrawal assay. The dose-response of intrathecal morphine (1-320 [mu]g) for both scratching and antinociception in all subjects was established. An opioid antagonist, nalmefene, was administered either intravenously or subcutaneously to assess its efficacy against intrathecal morphine.
Results: Intrathecal morphine (1-32 [mu]g) increased scratching in a dose-dependent manner. Higher doses of intrathecal morphine (10-100 [mu]g) produced thermal antinociception in a dose-dependent manner. On the other hand, nalmefene (10-32 [mu]g/kg intravenously) attenuated maximum scratching responses among subjects. Pretreatment with nalmefene (32 [mu]g/kg subcutaneously) produced approximately 10-fold rightward shifts of intrathecal morphine dose-response curves for both behavioral effects. 相似文献
Methods: In experiment 1, each group of rats received the GR antagonist RU38486 (0.5 or 1 [mu]g), the mineralocorticoid receptor antagonist spironolactone (3 [mu]g), or a vehicle, given intrathecally with morphine (10 [mu]g) twice daily for 6 days. In experiment 2, four groups of rats were used, and each group received intrathecally 10 [mu]g morphine plus 5 [mu]mol GR antisense oligodeoxynucleotide, sense oligodeoxynucleotide, mixed-base oligodeoxynucleotide, or vehicle. Western blotting was used to examine the expression of GRs within the spinal cord dorsal horn. In experiment 3, the GR agonist dexamethasone (4 [mu]g) was given intrathecally twice daily in combination with 10 [mu]g morphine. For all experiments, the development of morphine antinociceptive tolerance was assessed using the tail-flick test.
Results: The development of tolerance to the antinociceptive effect of morphine was substantially attenuated when the GR antagonist RU38486 (1 > 0.5 [mu]g > vehicle) but not spironolactone was coadministered with morphine for 6 days. A single treatment with RU38486 did not affect morphine antinociception, nor did it reverse morphine tolerance on day 7. A similar reduction of morphine tolerance was observed in those rats treated with a GR antisense oligodeoxynucleotide but not a sense or mixed-base oligodeoxynucleotide. The administration of the GR antisense oligodeoxynucleotide also prevented GR up-regulation within the spinal cord dorsal horn. Moreover, the GR agonist dexamethasone facilitated the development of morphine tolerance. 相似文献
Methods: Endotoxin was infused at doses of 1, 2 and 10 [mu]g/kg over 1 h to rats on day 14 of pregnancy. Mean arterial pressure, urinary protein, urinary and plasma nitrite plus nitrate (NO2- + NO3-) concentrations, and platelet count were measured before and after the endotoxin infusion. In another group of pregnant rats, the nitric oxide synthase inhibitor l-nitroarginine methyl ester (l-NAME) was administered in drinking water at a dose of 3 mg [middle dot] kg-1 [middle dot] d-1 starting on day 7 of pregnancy. Endotoxin was then infused at 10 [mu]g/kg on day 14 of pregnancy. Kidneys and uteroplacental units were examined histologically and analyzed immunohistochemically for 3-nitrotyrosine.
Results: Endotoxin administration at doses of 2 and 10 [mu]g/kg caused proteinuria and thrombocytopenia in pregnant rats, but did not result in hypertension. Urinary NO2- + NO3- concentration, reflective of tissue [middle dot] NO production rates, was significantly elevated in pregnant rats that received endotoxin at 10 [mu]g/kg. Ingestion of l-NAME caused hypertension. Tissues from pregnant rats treated with l-NAME, endotoxin at 10 [mu]g/kg, and a combination of l-NAME and endotoxin had increased 3-nitrotyrosine immunoreactivity. 相似文献
Methods: Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 [mu]g [middle dot]kg-1 [middle dot]min-1 (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 [mu]g [middle dot] kg-1 [middle dot] min-1 until skin closure and then 2 [mu]g [middle dot]kg-1 [middle dot]min-1 for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h.
Results: Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects. 相似文献
Methods: Thirty children, 9-19 yr of age, scheduled for spinal fusion, were randomly allocated into three groups to receive a single dose of 0 (saline injection), 2, or 5 [mu]g/kg intrathecal morphine. After surgery, a patient-controlled analgesia device (PCA) provided free access to additional intravenous morphine. Children were monitored for 24 h in the postanesthesia care unit.
Results: The three groups were similar for age, weight, duration of surgery, and time to extubation. The time to first PCA demand was dose-dependently delayed by intrathecal morphine. The first 24 h of PCA morphine consumption was 49 +/- 17, 19 +/- 10, and 12 +/- 12 mg (mean +/- SD) in the saline, 2 [mu]g/kg morphine, and 5 [mu]g/kg morphine groups, respectively. Pain scores at rest were significantly lower over the whole study period after 2 and 5 [mu]g/kg intrathecal morphine than after saline, but there was no difference between intrathecal doses. Pain scores while coughing and the incidence of side effects were similar in the three groups. 相似文献
Methods: Adult male Sprague-Dawley rats (n = 18) were anesthetized with isoflurane. One microdialysis probe was placed in the substantia innominata region of the basal forebrain and perfused with Ringer's solution (control) followed by one concentration of morphine (1, 10, 100, or 1,000 [mu]m) or morphine (1,000 [mu]m) plus naloxone (100 [mu]m). A second microdialysis probe was placed in the prefrontal cortex for measuring acetylcholine. In a second series of experiments, rats (n = 6) were implanted with electrodes for recording states of arousal, a guide cannula positioned above the prefrontal cortex for inserting a microdialysis probe, and an indwelling jugular vein catheter. The effects of administering intravenous morphine (30 mg/kg) versus normal saline (0.9%) on prefrontal cortical acetylcholine release, cortical electroencephalographic power, and behavior were quantified.
Results: Dialysis delivery of morphine to the substantia innominata caused a concentration-dependent, naloxone-sensitive decrease in acetylcholine release within the prefrontal cortex. The maximal decrease in acetylcholine was 36.3 +/- 11.5%. Intravenous morphine administration significantly decreased cortical acetylcholine release, increased electroencephalographic power in the 0.5- to 5-Hz range, and eliminated normal wakefulness. 相似文献
Methods: Mononeuropathy was induced by placing four ligatures around the common sciatic nerve. The 4-day pretreatment regimens with two daily subcutaneous injections of saline and saline, saline and morphine (10 mg/kg), (+)-HA966 (2.5 mg/kg) and morphine, or (+)-HA966 and saline were begun on postoperative day 12 to test the ability of (+)-HA966 to prevent the development of tolerance. Behavioral experiments were performed on postoperative day 16, when the pain-related behavior reached a stable maximum. The effect of an acute dose of morphine (1 mg/kg intravenously) was tested against both mechanical (vocalization threshold to paw pressure) and thermal (struggle latency to hind paw immersion into a 46[degrees]C hot-water bath) stimuli. In addition, to test the ability of a single injection of (+)-HA966 to reverse established morphine tolerance, groups of morphine-pretreated rats received injections of either (+)-HA966 (2.5 mg/kg subcutaneously) and morphine (1 mg/kg intravenously), saline and morphine, or (+)-HA966 and saline.
Results: Baseline vocalization thresholds and struggle latencies did not differ in the various pretreatment groups, indicating that the pretreatments had no effect on pain-related behavior. Coadministration of (+)-HA966 prevented the reduction of the effect observed with morphine alone in both the mechanical test and the thermal test. (+)-HA966 reversed morphine tolerance in the thermal but not in the mechanical test. 相似文献
Methods: Experiments were performed in mice lacking exon 2 of the [mu]OR gene ([mu]OR-/-) and their wild-type littermates ([mu]OR+/+). The influence of saline, morphine, naloxone, and sevoflurane on respiration was measured using a whole body plethysmographic method during air breathing and elevations in inspired carbon dioxide concentration. The influence of morphine and naloxone on anesthetic potency of sevoflurane was determined by tail clamp test.
Results: Relative to wild-type mice, [mu]OR-deficient mice displayed approximately 15% higher resting breathing frequencies resulting in greater resting ventilation levels. The slope of the ventilation-carbon dioxide response did not differ between genotypes. In [mu]OR+/+ but not [mu]OR-/- mice, a reduction in resting ventilation and slope, relative to placebo, was observed after 100 mg/kg morphine. Naloxone increased resting ventilation and slope in both genotypes. Sevoflurane at 1% inspired concentration induced similar reductions in resting ventilation and slope in the two genotypes. Anesthetic potency was 20% lower in mutant relevant to wild-type mice. Naloxone and morphine caused an increase and decrease, respectively, in anesthetic potency in [mu]OR+/+ mice only. 相似文献
Methods: Dogs were prepared with lumbar intrathecal catheters and vest-mounted pumps. To define the time course of granuloma formation, serial magnetic resonance imaging was performed in animals receiving 10 or 31 days of morphine infusion (12.5 mg/ml at 40 [mu]l/h). At these times, morphine was removed from the infusate, and further magnetic resonance images were acquired over 14-35 additional days. To assess dose versus concentration, dogs received 28-day infusions of vehicle, 12 mg morphine/day as 12.5 mg/ml at 40 [mu]l/h, or 1.5 mg/ml at 334 [mu]l/h (12 mg/day) for 28 days. Additional dogs received 3 mg/day as 12.5 mg/ml at 10 [mu]l/h.
Results: Serial magnetic resonance images in dogs receiving morphine (12.5 mg/ml at 40 [mu]l/h) revealed pericatheter-enhancing tissues as early as 3 days with a prominent signal by 10 days. Removal of morphine reduced the mass volume within 7 days. At a fixed infusion rate, the incidence of granuloma formation with the continuous intrathecal infusion of morphine ranged from 0 in vehicle-treated dogs to 100% in dogs treated with 12.5 mg/ml at 40 [mu]l/h (12 mg/day). Infusion of 12 mg/day at 1.5 mg/ml (334 [mu]l/h) resulted in granuloma in one of four animals. The authors found that infusion of morphine in different concentrations at a fixed rate resulted in a dose-dependent increase in concentration, with the granuloma-producing, dose-yielding lumbar cerebrospinal fluid morphine concentrations around 40 [mu]g/ml. 相似文献
Methods: Rats were rendered diabetic with an intraperitoneal injection of streptozotocin. The nociceptive withdrawal threshold was measured before and after intrathecal injection of morphine by applying a noxious pressure stimulus to the hind paw. The [mu] opioid receptor was determined with immunocytochemistry labeling and a specific [mu] opioid receptor radioligand, [3H]-(d-Ala2,N-Me-Phe4,Gly-ol5)-enkephalin ([3H]-DAMGO), in the dorsal spinal cord obtained from age-matched normal and diabetic rats 4 weeks after streptozotocin treatment.
Results: The antinociceptive effect of intrathecal morphine (2-10 [mu]g) was significantly reduced in diabetic rats, with an ED50 about twofold higher than that in normal rats. However, both the dissociation constant (3.99 +/- 0.22 vs. 4.01 +/- 0.23 nm) and the maximal specific binding (352.78 +/- 37.26 vs. 346.88 +/- 35.23 fmol/mg protein) of [3H]-DAMGO spinal membrane bindings were not significantly different between normal and diabetic rats. The [mu] opioid receptor immunoreactivity in the spinal cord dorsal horn also was similar in normal and diabetic rats. 相似文献
Methods: Rats were implanted with intravenous and intrathecal catheters. The antinociceptive effect of morphine was determined by the paw-withdrawal latency in response to a radiant heat stimulus after intrathecal treatment with atropine (a muscarinic receptor antagonist), mecamylamine (a nicotinic receptor antagonist), or cholinergic neurotoxins (ethylcholine mustard aziridinium ion [AF64A] and hemicholinium-3).
Results: Intravenous injection of 2.5 mg/kg morphine increased significantly the paw-withdrawal latency. Intrathecal pretreatment with 30 [mu]g atropine (n = 7) or 50 [mu]g mecamylamine (n = 6) both attenuated significantly the antinociceptive effect of morphine. The inhibitory effect of atropine on the effect of morphine was greater than that of mecamylamine. Furthermore, the antinociceptive effect of morphine was significantly reduced in rats pretreated with intrathecal AF64A (n = 7) or hemicholinium-3 (n = 6) to inhibit the high-affinity choline transporter and acetylcholine synthesis. We found that intrathecal AF64A reduced significantly the [3H]hemicholinium-3 binding sites but did not affect its affinity in the dorsal spinal cord. 相似文献
Method: Tolerance was produced in mice given morphine subcutaneously and was assessed by a cumulative dose-response analysis using the tail-flick test. The ability of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and after morphine to attenuate the development of tolerance was assessed. The ability of 10 mg/kg ketamine to reverse tolerance produced by the subcutaneous implantation of morphine pellets to mice was also assessed. Rats were made tolerant to intraspinal morphine and the effects of the coadministration of 12 micro gram intraspinal ketamine were assessed.
Results: Morphine given subcutaneously produced a fivefold increase in the median effective (ED50) dose of morphine, which was dose-dependently attenuated by subcutaneously administered ketamine. A tenfold increase in the morphine ED50 produced by morphine pellets was completely reversed by ketamine given subcutaneously. Intraspinal morphine produced a 46-fold increase in its ED50, which was almost completely attenuated by the coadministration of intraspinal ketamine. 相似文献
