The antinociceptive effect of tramadol-venlafaxine combination on the paw withdrawal threshold in a rat model of neuropathic pain

The combination of venlafaxine and tramadol was compared with the single use of these agents to investigate the antinociceptive effect on paw withdrawal latency (PWL) to paw pressure in rats with neuropathic pain. Rats were divided into 4 groups: group 1 received saline (0.2 ml i.p.); group 2 received venlafaxine (22 mg/kg i.p.); group 3 received tramadol (20 mg/kg i.p.); and group 4 received venlafaxine + tramadol. No statistically significant changes were observed in the saline and venlafaxine groups with respect to PWL in the lesioned paw. However, tramadol produced a significant antinociceptive effect on the lesioned paw at 30 min compared with the saline and venlafaxine groups. A more potent antinociceptive effect was observed in the tramadol + venlafaxine group, beginning at 60 min and lasting for 1 h. The combination of venlafaxine + tramadol was more effective in increasing the pain threshold in this animal model of neuropathic pain than either of these drugs administered alone.     

The antinociceptive effect of moclobemide on the vocalization threshold to paw pressure in a rat model of unilateral mononeuropathy

The aim of our study was to investigate the antinociceptive activity of moclobemide on the vocalization threshold to paw pressure in a rat model of unilateral mononeuropathy. The neuropathy was produced by ligation of the sciatic nerve and nociceptive thresholds were determined 15-21 days after surgery by a modification of the Randall-Sellito method. Group 1 (n= 10) received 0.2 ml peroral (p.o.) saline, Group 2 (n= 10) 5 mg x kg(-1), Group 3 (n= 10) 10 mg x kg(-1) and Group 4 (n= 10) 20 mg x kg(-1) p.o. moclobemide. Nociceptive pressure thresholds were then measured every 20 minutes after drug administration. Analysis of variance, Tukey's test and a paired Student's t-test were employed for statistical analysis. The perorally administered moclobemide (5, 10 and 20 mg x kg(-1)) produced an antinociceptive effect on both lesioned and non-lesioned hind paws ( P< 0.05). However, the analgesic effect on the lesioned paw was significantly more potent than the non-lesioned paw. The peak value ( p) remained constant while the maximal increment between the control threshold and the peak value ( I(max)) was significantly more pronounced for the lesioned paw ( P< 0.001). The results of this study may suggest that moclobemide can be a therapeutic alternative to treat some clinical symptoms in peripheral neuropathic conditions.     

Mechanism of antinociceptive effect of nimodipine in experimental diabetic neuropathic pain

This study used streptozotocin-(STZ; 50 mg/kg, i.v.) diabetic rats and monitored the weekly thermal nociceptive thresholds for 8-week diabetes. Nimodipine (10 mg/kg i.p.) treatment initiated after 8 weeks of diabetes antagonized the hyperalgesic response in diabetic rats. However, insulin treatment showed a partial response in these animals. Thermal hyperalgesia showed reduced sensitivity to the antinociceptive effect of morphine (5 mg/kg, i.p.). Furthermore, a reduced sensitivity to the antinociceptive effect of baclofen (GABAB agonist; 4 mg/kg i.p.) was observed. Five days of treatment with MK-801 (N-methyl-D-aspartate [NMDA] receptor antagonist 0.5 mg/kg i.p.) completely reversed 8-week diabetes-induced thermal hyperalgesia. These data suggest that diabetes-induced hyperalgesia may be the consequence of increased excitatory tone within the spinal cord. An increased release of glutamate and activation of the NMDA receptor would maintain the hyperalgesic state. Reduced activity of both opioidergic and GABAB ergic inhibitory systems might accelerate the increased excitation, thus contributing to the ongoing pain in diabetic rats.     

长期高脂、高糖、高盐饮食对大鼠热和机械痛阈的影响

目的:观察长期高脂、高糖、高盐饲料饲养对正常大鼠热痛阈和机械痛阈的影响。方法:5周龄雄性SD大鼠30只,体重(100±5)g,随机分为高脂、高糖、高盐饲养组为A组(n=20)和正常饲养组为B组(n=10)。两组大鼠每日摄食、饮水不限。第1,10,20,30,40,50,60,70,120天时测量两组大鼠空腹血糖(fasting blood glucose,FBG)、空腹胰岛素(the fasting insulin,FINS)、热刺激缩足反应潜伏期(paw withdrawal thermallatency,PWTL)、机械刺激缩足反应阈值(pawwithdrawal mechanical threshold,PWMT)、体重、血压。结果:(1)A、B组大鼠空腹血糖均没有发生变化。(2)A组大鼠空腹血清胰岛素在20、30、40、50、60、70、120d明显升高,比较有明显差异(P<0.05),B组大鼠没有明显变化;(3)A组大鼠PWTL在70d以后出现明显下降(P<0.05),B组大鼠PWTL没有明显变化;(4)A组大鼠PWMT在60d出现明显下降(P<0.05),B组大鼠PWMT没有明显变化;(5)A组大鼠血压在20、30、40、50、60、70、120d明显高于B组,比较有明显差异(P<0.05);(6)A组大鼠体重与B组大鼠体重同时升高,在70d以后出现明显差异(P<0.05)。结论:高脂、高糖、高盐饲料饲养大鼠可以导致大鼠高血压,高胰岛素血症和胰岛素抵抗现象(饲养20d后)。在高脂、高糖、高盐饲料喂养下大鼠出现热痛敏(70d)和机械痛敏(60d),但与高血压、高胰岛素以及胰岛素抵抗现象不同时程出现。     

Development of tolerance to the antinociceptive effect of metergoline

Metergoline given IP reduced the response to noxious stimulation in the mouse formalin test. Tolerance to this effect developed after a chronic treatment schedule consisting of ten daily injections of 5 mg/kg. Twenty four hours after the last injection a test dose of metergoline (2.5 mg/kg) reduced the licking time in the formalin test by 28% in the chronic metergoline group, compared to 68% reduction in the vehicle-treated animals. In addition, the antinociceptive effect of the 5-hydroxytryptamine releasing compoundp-chloroamphetamine (PCA) was reduced following chronic treatment with metergoline. The reduced effect of PCA may have been caused by down-regulation of 5-HT₂ receptors. However, this finding is also compatible with the contention that metergoline may act as an agonist at postsynaptic serotonergic receptors.     

Enhancement of antinociceptive effect of morphine by antidepressants in diabetic neuropathic pain model

BackgroundRecent studies have shown that influence of antidepressants on analgesic action of opioids is heterogeneous. The aim of this study was to investigate the effect of acute and repeated (21 days) antidepressant (amitriptyline, moclobemide and reboxetine) treatment on the antinociceptive action of morphine, an opioid agonist, in streptozotocin (STZ)-induced neuropathic pain model.MethodsThe studies were performed on the male Wistar rats. The changes in nociceptive thresholds were determined by using mechanical stimuli (the Randall–Selitto and the von Frey tests). Diabetes was induced by intramuscular administration of STZ.ResultsIn this work we report that acute as well as repeated per os administration of antidepressants (amitriptyline, moclobemide and reboxetine) significantly potentiated the antihyperalgesic effect of morphine in STZ-induced neuropathic pain model.ConclusionCombination therapy, such as classical antidepressants (amitriptyline, moclobemide) with opioids, or agents with noradrenaline reuptake inhibition and μ-opioid receptor activation could be a new target for research into treatment of painful diabetic neuropathy.     

Tolerance to the antinociceptive effect of morphine in the spinal rat

Tolerance and withdrawal were studied in spinal and intact rats receiving morphine hydrochloride (10–20 mg/kg, i.p.) every 12 hr for 10 days. All rats developed tolerance to morphine-induced antinociception measured by the tail-flick method. Tolerance was not reversed by d,l-5-hydroxytryptophan (200 mg/kg, i.p.). Naloxone (1–2 mg/kg) induced signs of withdrawal both in spinal and intact rats. Thus, functional changes in the aminergic systems and in brain and brainstem structures appear not to be necessary for tolerance to morphine-induced antinociception and for dependence on morphine. The experiment does not support the hypothesis that conditioning to environmental stimuli and changes in cognitive functions play a major role in tolerance development in the rat.     

Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of baclofen in mice.

The aim of this study was the development of a pharmacokinetic-pharmacodynamic (PK/PD) model of the antinociceptive effect of baclofen in mice. We studied the dose response curve of the analgesic action of baclofen in mice by hot plate test. Baclofen produced a dose dependent antinociceptive effect with doses between 1-3 mg/kg administered intraperitoneally (i.p.) (ED50: 1.94 mg/kg of racemate) and this effect fits to a linear pharmacodynamic model. Blood and brain concentrations of (-)3H-baclofen were determined by Thin-Layer Chromatography (TLC) and counted in the scintillation-counter. The PK/PD models were analyzed with the PC-TOPFIT V.2.0 and the tests for distinguishing between models were several adjustment parameters as Akaike information criterion (AIC), Imbimbo criterion (Ip), standard deviation (SD) and the correlation coefficient (r2). Accordingly with these adjustment parameters, a 2 compartment open model was selected where plasma is the central compartment and brain is in the peripheral compartment. In this model, the effect is linked to the peripheral compartment. When the antinociceptive effect of baclofen was plotted against blood concentration, the resulting curve exhibited an anticlockwise hysteresis loop, but on the other hand, when the antinociceptive effect was plotted against the brain concentration, the hysteresis was collapsed. These results confirmed the selected model in our study, as the best adjustment was shown when the pharmacological response was linked to the peripheral compartment.     

The periaqueductal gray is the site of the antinociceptive action of carbamazepine as related to bradykinin-induced trigeminal pain.

Using freely moving and conscious rats, the antinociceptive effects of microinjections of carbamazepine, into the periaqueductal gray (PAG), nucleus reticularis paragigantocellularis (NRPG) and nucleus raphé magnus (NRM) on the biting-like responses induced by bradykinin applied to the tooth pulp, were investigated to determine the primary site of action of this drug. Microinjections of carbamazepine into the PAG ipsi- and contralateral to the stimulated tooth pulp produced dose-dependent suppressive effects on the biting-like responses within 1 min. The ED50 was 1.57 micrograms per rat, that is about 1,500 times less than that for carbamazepine administered systemically. The antinociceptive effect of carbamazepine administered into the PAG was inhibited by pretreatment with bicuculline but not by phentolamine, propranolol and haloperidol. Microinjections of carbamazepine into the NRPG and NRM were rarely effective in the production of antinociception at doses used (up to 3 micrograms per rat). These results suggest that the PAG is one of the primary target sites for the antinociceptive activity of carbamazepine, and that GABAergic systems are involved this action of carbamazepine.     

鞘内注射氟代柠檬酸对炎性痛敏大鼠的镇痛作用

目的研究鞘内注射氟代柠檬酸(fluorocitrate,Fc)对致炎大鼠痛觉过敏的影响。方法采用大鼠右后爪踝关节外侧皮下注射完全弗氏佐剂(complete freunds adjuvant,CFA)50μl致炎模型。测定给予CFA或Fc前后大鼠机械性缩爪阈值(MWT)和热刺激缩爪潜伏期(TWL)。免疫组化分析脊髓背角星形胶质细胞标记物(GFAP)和小胶质细胞标记物(OX-42)的表达。结果大鼠皮下注射CFA24h后出现明显的炎性痛敏,鞘内注射Fc后4,6,8,10,12h,与CFA组大鼠比较,大鼠MWT明显提高(P<0.01),TWL明显延长(P<0.01)。鞘内注射Fc6h后,降低脊髓背角GFAP和OX-42表达。结论脊髓胶质细胞可能参与炎性痛敏的发生和维持,氟代柠檬酸可能通过抑制其生物活性而发挥镇痛作用。     

Possible involvement of opioidergic and serotonergic mechanisms in antinociceptive effect of paroxetine in acute pain

Antidepressant drugs, especially tricyclics have been widely used in the treatment of chronic pain, but not in acute pain. Because of numerous undesirable side effects, the selective serotonin reuptake inhibitors (SSRIs), with their favorable side effect profile, are preferred nowadays. An activation of the endogenous opioid mechanisms or potentiation of the analgesic effect mediated by serotonergic and/or noradrenergic pathways are thought to be involved in the antinociceptive action of SSRIs. In this study, the potential antinociceptive effect of paroxetine and its interaction with opioidergic system and serotonin receptors were evaluated. The antinociceptive effect of paroxetine was tested using a hot plate test in mice. Paroxetine, a SSRI antidepressant drug, induced an antinociceptive effect following i.p. administration. This antinociception was significantly inhibited by naloxone, an opioid receptor antagonist, suggesting the involvement of opioidergic mechanisms. While ondansetron (a 5-HT(3)-receptor antagonist) inhibited the effect of paroxetine, ketanserin (a 5-HT(2)-receptor antagonist) could not. In conclusion, paroxetine-induced antinociception, similar to morphine, suggests an involvement of direct or indirect action (via an increase in release of endogenous opioid peptide(s)) at opioid receptor sites and an involvement of serotonergic mechanisms mainly at the receptor level.     

The effect of amiodarone on the ventricular fibrillation threshold.

We evaluated the antifibrillatory effect of two different doses of amiodarone after cardiac arrest with a cardiopulmonary resuscitation (CPR) model in 19 pigs. Ventricular fibrillation was induced by pacing the right ventricle using a primary drive train at a cycle length of 270 msec for 8 beats. The minimum current strength necessary to induce sustained ventricular fibrillation was defined as the ventricular fibrillation threshold (VFT) measured in mA. Three VFT determinations were made at baseline, followed by 9 minutes of continuous CPR with two determinations of VFT, and three after stabilization. The pigs were placed into one of three groups: amiodarone 2 or 5 mg/kg, or placebo. The average poststabilization VFT in each group was compared with the average baseline VFT. Pigs receiving amiodarone 2 mg/kg had significantly higher VFT after stabilization than at baseline (22.88+/-12.76 to 27.10+/-10.18 mA, p=0.048), as did those receiving 5 mg/kg (17.03+/-7.01 to 28.08+/-11.58 mA, p=0.002). The deltaVFT was significantly greater with amiodarone 5 mg/kg than with vehicle (placebo), but not with 2 mg/kg. There were no changes in VFT in any group during CPR versus baseline. When active treatments were combined, the trend was toward better survival in the amiodarone groups (13/13) compared with the placebo group (4/6, p=0.076).     

Development of tolerance to the antinociceptive effect of mescaline intraventricularly administered to rabbits

The thymoleptics imipramine, desipramine, protriptyline, nortriptyline, chlorimipramine and amitriptyline all potentiate gnawing of mice induced by Dopa following the decarboxylase inhibitor Ro 4-4602.The gnawing behaviour is probably associated with the increase in brain dopamine resulting from this treatment. Thymoleptics also affect other types of behaviour associated with brain dopamine. The relevance of these effects to clinical antidepressive effect and their possible utilization for preclinical screening tests is discussed.     

The dissociation of the antinociceptive effect of clonidine from supraspinal structures.

The tail flick assay was used to assess the antinociceptive effects of morphine and clonidine in control and T₆-T₈ spinally transected mice. In spinalized mice the morphine ED₅₀ was increased 4–7 fold while the clonidine ED₅₀ was not significantly altered. These results indicate a clear separation of the principle sites for the antinociceptive activity of morphine and clonidine in this test.     

Analysis of the antinociceptive effect of systemic administration of tramadol and dexmedetomidine combination on rat models of acute and neuropathic pain

The aim of the present study was to investigate the possible antinociceptive effect of systemic administration of tramadol and dexmedetomidine either alone or in combination on acute and neuropathic pain models in rats. The antinociceptive effects of intraperitoneal (i.p.) tramadol (5-20 mg/kg) and dexmedetomidine (5-20 microg/kg) and three different combinations of tramadol+dexmedetomidine (5+5, 5+10 and 10+5, mg/kg+microg/kg, respectively) were measured by tail-flick and hot-plate methods in acute pain. The effects on the sciatic nerve ligation-induced neuropathic pain was tested by i.p. administration of tramadol (5 mg/kg), dexmedetomidine (5 microg/kg) and tramadol+dexmedetomidine combination (5+5) using a thermal plantar test. Sedation/motor-incoordination was assessed on rotarod. Tramadol and dexmedetomidine produced dose-related antinociception in tail-flick and hot-plate tests. In both tests, combination of these drugs produced an antinociceptive effect that is greater than that produced by tramadol or dexmedetomidine alone at several time points. In hot-plate test, tramadol+dexmedetomidine combination (5+10) exerted the strongest antinociceptive effect, while tramadol+dexmedetomidine combination (10+5) was significantly most effective in tail-flick test. In the neuropathic pain, the antinociceptive effect exerted by tramadol+dexmedetomidine combination (5+5) was also significantly greater than their applications alone. In rotarod test, tramadol (30 and 40 mg/kg), dexmedetomidine (30 and 40 microg/kg), tramadol+dexmedetomidine combination (10+10, 20+20) produced sedation/motor-incoordination, whereas tramadol (5-20 mg/kg), dexmedetomidine (5-20 microg/kg) and tramadol+dexmedetomidine combination (5+5, 5+10 and 10+5) did not produce any effect on sedation/motor-incoordination. The combination of tramadol and dexmedetomidine was more effective in increasing the pain threshold in acute and neuropathic pain when compared with the administration of either of these drugs alone.     

Tolerance to antinociceptive effects of morphine without tolerance to its effects on schedule-controlled behavior

The development of tolerance to behavioral effects of morphine was investigated in rats that responded on a two-lever, multiple-trial, multiple differential-reinforcement-of-low-rate fixed-ratio (mult DRL FR) schedule of food presentation. Stable performances were maintained when sessions were conducted just twice per week. The effects of cumulative doses of morphine (1.0–8.0 mg/kg) or chlordiazepoxide (CDP; 4.0–32.0 mg/kg) were evaluated once per week; saline injections were given in the intervening sessions. The effects of saline and morphine on nociception were also evaluated in hot-plate tests conducted on the same subjects 15 min after selected operant sessions. Initially, morphine produced dose-related decreases in response rates and reinforcement rates in the DRL and FR components as well as significant increases in hot-plate response latencies. Following weekly administration of morphine (1.0–8.0 mg/kg) for 10 weeks, there was little or no tolerance to its effects on operant behavior. In contrast, complete tolerance developed to the antinociceptive effects of morphine. These results suggest that tolerance to various behavioral effects of morphine may be dissociated, and that the loss of reinforcement may be insufficient by itself to produce tolerance to effects of morphine on operant behavior. Additionally, whereas CDP initially produced only dose-related decreases in DRL and FR response rates, following weekly morphine the smaller doses of CDP (4.0–16.0 mg/kg) produced increases in response rates. Finally, the effects of cumulative doses of morphine did not differ significantly from the effects of noncumulative doses of the drug.