Skin nociceptive block with pramoxine delivery by subcutaneous injection in rats

Background

Pramoxine has been shown to produce spinal anesthesia, while cutaneous analgesia (peripheral) of pramoxine is not established. The experimental goal was to examine cutaneous antinociception produced by a local anesthetic (LA) pramoxine and compare this result with that of another well-known LA lidocaine.

Modification of local anesthetic-induced antinociception by fentanyl in rats

In clinical practice, using the lowest doses of drugs for anesthesia or analgesia is the main goal. Opioid combinations with local anesthetics can be preferable for achieving adequate anesthesia or analgesia. The primary purpose of this study was to examine possible thermal antinociceptive effects of the opioid -fentanyl and the amide local anesthetics levobupivacaine and lidocaine when locally administered alone or in combination. The paw withdrawal latencies to noxious thermal stimuli in rats were measured to assess the antinociceptive actions of drugs after subcutaneous intraplantar injection into the hind paw. All drugs examined in this study produced dose- and time-dependent increases in the paw withdrawal latencies. Fentanyl is approximately 125 and 500 times more potent than levobupivacaine and lidocaine, respectively. At the same dose, the antinociceptive potency of levobupivacaine was 3.6-fold higher than that of lidocaine. Co-injection of the lowest doses of levobupivacaine and lidocaine dramatically increased the paw withdrawal latency. However, in the presence of fentanyl, the effects of levobupivacaine and lidocaine were different. Although co-injection of levobupivacaine with fentanyl both enhanced and prolonged antinociceptive action, the lidocaine-fentanyl combination did not significantly change the paw withdrawal latency. These results suggest that intraplantar co-administration of fentanyl with levobupivacaine, but not lidocaine, may provide more effective antinociception without increasing the dose requirements.     

Effects of haloperidol on morphine-induced antinociception morphine tolerance and withdrawal in hyperprolactinaemic rats

Male rats with hyperprolactinaemia, induced by adenohypophyseal homografts under the kidney capsule, were injected with haloperidol for 3 days and then subjected to treatment with morphine, administered twice in a day at increasing doses for 12 days. At the first treatment, morphine induced an antinociceptive effect that was more prolonged in homografted rats than in sham-operated controls. The pretreatment with haloperidol did not change the prolongation of morphine-induced antinociception in homografted rats. After 12 days of treatment with morphine, all animals were tested for the development of tolerance to the antinociceptive effect of morphine. Pituitary homografts resulted in an inhibition of the development of tolerance, while this effect was absent in homografted rats pretreated with haloperidol. At the end of the treatment with morphine, the naloxone-precipitated abstinence syndrome was studied. Homografted rats shown an attenuation of the withdrawal syndrome and pretreatment with haloperidol did not change this response.These results suggest an involvement of dopaminergic transmission in prolactin-induced changes in the development of tolerance to morphine, but not in the antinociceptive effect following an acute injection of morphine and in naloxone-precipitated withdrawal syndrome of the rat.     

Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine

RATIONALE: Inhibitors of neuronal dopamine uptake, such as GBR 12909, decrease IV cocaine self-administration by laboratory animals and have been proposed as potential therapeutic agents for abuse of psychomotor stimulant drugs. OBJECTIVES: This study was performed to determine how GBR 12909 alters the discriminative stimulus effects of methamphetamine and cocaine. METHODS: Rats were trained to discriminate between IP injections of 10 mg/kg cocaine and saline and were tested for stimulus generalization to cocaine, GBR 12909, and methamphetamine. Based upon the ED50 of the individual drugs, combinations of GBR 12909 and either cocaine or methamphetamine were tested that comprised a) 1 part GBR 12909 and 2 parts cocaine or methamphetamine, or b) 2 parts GBR 12909 and 1 part cocaine or methamphetamine. RESULTS: GBR 12909 and cocaine were equipotent and 30-fold less potent than methamphetamine in producing cocaine-like discriminative effects. GBR 12909 and cocaine produced cocaine-like discriminative effects synergistically in the ratio of 1 part GBR 12909:2 parts cocaine (0.16+0.32 to 1.92+ 3.87 mg/kg) and nearly synergistically in the ratio of 2 parts GBR 12909:1 part cocaine (0.32+0.16 to 3.92+ 1.91 mg/kg). GBR 12909 and methamphetamine (0.32+0.02 to 3.20+0.22 mg/kg or 0.65+0.01 to 6.53+0.1 mg/kg) were simply additive in both sets of fixed-ratio dose combinations. CONCLUSIONS: The synergy of GBR 12909 and cocaine and the additivity of GBR 12909 and methamphetamine run counter to the presumed mechanisms of action of these drugs at dopamine nerve terminals, which might have implications for the use of GBR 12909 in the treatment of addiction to cocaine or amphetamines.     

鞘内注射哌唑嗪对氯胺酮抗伤害作用的影响

目的　探讨脊髓α1 受体和氯胺酮(Ket, 37. 5mg·kg-1,ip)抗伤害作用的关系。方法　用热水甩尾法观察大鼠鞘内预先注射α1 受体拮抗剂哌唑嗪(Pra, 10, 30μg)对Ket抗伤害作用的影响。并用c fos基因免疫组织化学技术,观察Ket对痛刺激诱发的大鼠脊髓c- fos表达的调节作用及鞘内预先注射Pra(30μg)对Ket调节作用的影响。结果　鞘内单独注射各剂量Pra对动物痛阈均无明显影响(P>0 .05), 鞘内预注Pra(10μg)对Ket抗伤害作用无明显影响(P>0 .05)。而鞘内预注Pra(30μg)则可明显减弱Ket抗伤害作用(P<0 .05)。痛刺激前给予Ket明显减少背角各层Fos免疫阳性神经元的数量(P<0 .05),Ket对痛刺激诱发的脊髓ⅠⅣ层c fos表达的抑制作用可被鞘内预注Pra所减弱(P<0 .05)。结论　脊髓α1 受体参与Ket抗伤害作用。     

Role of benzodiazepine and serotonergic mechanisms in conditioned freezing and antinociception using electrical stimulation of the dorsal periaqueductal gray as unconditioned stimulus in rats

Abstract Rationale. The dorsal periaqueductal gray matter (dPAG) has been implicated in the modulation of defensive behavior. Electrical stimulation of this structure can be used as an unconditioned stimulus to produce a conditioned fear reaction expressed by freezing, antinociception, and autonomic responses. Objectives. This study investigated the influence of benzodiazepine, serotonergic, and opioid mechanisms on these conditioned responses. Methods. Animals implanted with an electrode and a guide cannula into the dPAG were submitted to two conditioning sessions. Each session consisted of ten pairings of the light in a distinctive chamber (CS) with the electrical stimulation of this structure at the escape threshold. On the next day, each animal was exposed only to the CS (testing) and the duration of freezing, number of rearing and grooming episodes were recorded for 5 min. Before and after the testing session, animals were submitted to the tail-flick test. Fifteen minutes before the exposure to the CS, animals received injections into the dPAG of midazolam (a positive modulator of benzodiazepine sites), α-methyl-5-hydroxytryptamine (α-Me-5-HT; an agonist of 5-HT₂ receptors), naltrexone (an opioid antagonist), or vehicle. Results. Conditioning with dPAG electrical stimulation caused significant increases in the time of freezing and conditioned antinociception. Injections of midazolam into the dPAG significantly inhibited freezing behavior and antinociception due to conditioning. Injections of α-Me-5-HT inhibited the effects of conditioning on freezing without affecting conditioned antinociception. Injections of naltrexone (13 nmol/0.2 μl) did not change any of the conditioned responses studied. Conclusions. (1) Conditioned freezing and antinociception are modulated by benzodiazepine mechanisms into dPAG. (2) 5-HT₂ receptors seem to regulate conditioned freezing behavior. However, conditioned antinociception was not affected by 13 nmol naltrexone. (3) Opioid mechanisms do not seem to be involved in the conditioned responses using electrical stimulation of the dPAG as unconditioned stimulus. Further studies with other opioid and 5-HT₂ receptor antagonists are still needed to confirm the conclusions drawn from the present work. Electronic Publication     

Effect of H1 blockers alone and in combination with morphine to produce antinociception in mice

Antinociception was assessed in male CD-1 mice by a modification of Haffner's tail-clamp procedure. The H1 blockers, including an ethylenediamine (pyrilamine), an ethanolamine (diphenhydramine), a phenothiazine (methdilazine), a piperazine (cyclizine) and an alkylamine (chlorpheniramine), all produced antinociception when given alone to mice and also caused potentiation when combined with morphine.     

Dopamine D1 and D2 antagonists attenuate amphetamine-produced enhancement of responding for conditioned reward in rats

It has been suggested that the dopamine D₁ receptor may play an important role in reward. The present study was undertaken to investigate the roles of dopamine D₁ and D₂ receptor subtypes in responding for conditioned reward. This was done by examining the effects of the D₁ antagonist SCH 23390 and the D₂ antagonists pimozide and metoclopramide on amphetamine-produced enhancement of responding for conditioned reward. The procedure consisted of three distinct phases. During the pre-exposure phase the rats were exposed to an operant chamber containing two levers. One lever produced a lights-off stimulus (3 s) and the other a tone stimulus (3 s). This was followed by four conditioning sessions during which the levers were removed and the rats were exposed to pairings of the lights-off stimulus with food. This phase was followed by two test sessions during which the levers were present and the number of responses made on each was calculated as a ratio of the number of responses made during the pre-exposure phase. A group receiving the vehicle during the test sessions showed a greater ratio of responding for the light-off stimulus than the tone stimulus, indicating that the lights-off stimulus had become a conditioned reward. Amphetamine (0.1, 1.0, 2.0 and 5.0 mg/kg, IP, 5 min prior to test) specifically enhanced responding on the lever producing conditioned reward. SCH 23390 (5.0 and 10.0 µg/kg, SC, 2 h before test) and pimozide (0.1 and 0.2 mg/kg, IP, 4 h before test) dose-dependently shifted the peak in the amphetamine dose-response function to the right, indicating an attenuation of conditioned reward. Metoclopramide (1.0, 5.0 and 7.5 mg/kg, IP, 1 h before test) reduced the amphetamine-produced enhancement of responding for conditioned reward but failed to shift the amphetamine dose-response function. These results provide evidence that both D₁ and D₂ receptor subtypes are essential in responding for conditioned reward.     

Dopamine D1 receptor agonists induce penile erections in rats

The dopamine receptor agonist apomorphine has been recently introduced in the treatment of erectile dysfunction. While it is well established that dopamine D2-like receptors play a crucial role in this effect, conflicting result are reported in the literature as for the role of dopamine D1-like receptors. The aim of this study was to determine the effect of systemic administration of dopamine D1-like receptor agonists on penile erection in rats. Male Wistar rats were treated with three different, and not structurally related, dopamine D1-like receptor agonists: the partial agonists SKF38393 ((+) 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) and CY 208-243 ((-)-4,6,6a,7,8,12b-exahydro-7-methylindole [4,3-ab]fenantridine), and the full agonist A 77636 ((-)-(1R,3S)-3-Adamantyl-1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran hydrochloride). All three compounds dose-dependently increased the number of penile erections, with the full agonist A77636 showing a more pronounced effect with respect to the other two. Moreover, the dopamine D1-like receptor antagonist SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) dose-dependently antagonised A77636 effect. These results show that systemic administration of dopamine D1-like receptor agonists induce penile erection in rats. This observation suggests that dopamine D1-like receptor agonists might be considered as a possible alternative to apomorphine in the treatment of erectile dysfunction, thus avoiding the typical side effects related to the stimulation of dopamine D2-like receptors such as nausea.     

Mechanisms involved in the antinociception induced by systemic administration of guanosine in mice

Background and purpose:

It is well known that adenine-based purines exert multiple effects on pain transmission. However, less attention has been given to the potential effects of guanine-based purines on pain transmission. The aim of this study was to investigate the effects of intraperitoneal (i.p.) and oral (p.o.) administration of guanosine on mice pain models. Additionally, investigation into the mechanisms of action of guanosine, its potential toxicity and cerebrospinal fluid (CSF) purine levels were also assessed.

Experimental approach:

Mice received an i.p. or p.o. administration of vehicle (0.1 mM NaOH) or guanosine (up to 240 mg·kg⁻¹) and were evaluated in several pain models.

Key results:

Guanosine produced dose-dependent antinociceptive effects in the hot-plate, glutamate, capsaicin, formalin and acetic acid models, but it was ineffective in the tail-flick test. Additionally, guanosine produced a significant inhibition of biting behaviour induced by i.t. injection of glutamate, AMPA, kainate and trans-ACPD, but not against NMDA, substance P or capsaicin. The antinociceptive effects of guanosine were prevented by selective and non-selective adenosine receptor antagonists. Systemic administration of guanosine (120 mg·kg⁻¹) induced an approximately sevenfold increase on CSF guanosine levels. Guanosine prevented the increase on spinal cord glutamate uptake induced by intraplantar capsaicin.

Conclusions and implications:

This study provides new evidence on the mechanism of action of the antinociceptive effects after systemic administration of guanosine. These effects seem to be related to the modulation of adenosine A₁ and A_2A receptors and non-NMDA glutamate receptors.     

Nanodesign of new self-assembling core-shell gellan-transfersomes loading baicalin and in vivo evaluation of repair response in skin

Gellan nanohydrogel and phospholipid vesicles were combined to incorporate baicalin in new self-assembling core-shell gellan-transfersomes obtained by an easy, scalable method. The vesicles were small in size (~107 nm) and monodispersed (P.I. ≤ 0.24), forming a viscous system (~24 mPa/s) as compared to transfersomes (~1.6 mPa/s), as confirmed by rheological studies. Gellan was anchored to the bilayer domains through cholesterol, and the polymer chains were distributed onto the outer surface of the bilayer, thus forming a core-shell structure, as suggested by SAXS analyses. The optimal carrier ability of core-shell gellan-transfersomes was established by the high deposition of baicalin in the skin (~11% in the whole skin), especially in the deeper tissue (~8% in the dermis). Moreover, their ability to improve baicalin efficacy in anti-inflammatory and skin repair tests was confirmed in vivo in mice, providing the complete skin restoration and inhibiting all the studied inflammatory markers.     

Sex-related differences in the enhancement of morphine antinociception by NMDA receptor antagonists in rats

The effect of the N-methyl-D-aspartate (NMDA) receptor antagonists dextromethorphan (DEX), ketamine (KET), and MK-801 on morphine (MOR)-induced antinociception has been investigated in male and female rats. DEX (7.5, 15, and 30 mg/kg), KET (0.75, 1.5, and 3 mg/kg), and MK-801 (0.075, 0.15, and 0.3 mg/kg) dose-dependently enhanced MOR-induced (3 mg/kg) analgesia in female rats. DEX and KET enhanced the peak effect, whereas MK-801 increased both magnitude and duration of analgesia. DEX also enhanced MOR-induced analgesia in male rats. However, the interaction was of less magnitude in male compared with female rats. The effects of KET and MK-801 on MOR-induced analgesia were negligible in male rats. A 3-mg/kg dose of MOR given alone produced greater analgesia in male than in female rats, but in the presence of NMDA antagonists, MOR elicited similar analgesic responses in both sexes.     

Dopamine on D2-like receptors is involved in reward evaluation in water-deprived rats licking for NaCl and water

The analysis of licking microstructure provides measures, size and number of licking bouts, which might reveal, respectively, reward evaluation and behavioural activation. Based on the ability of the dopamine D2-like receptor antagonist raclopride to reduce bout size and to induce an “extinction mimicry effect” on bout number, we suggested that the level of activation of reward-associated responses is updated, or “reboosted”, on the basis of a dopamine D2-like receptor-mediated evaluation process occurring during the consummatory transaction with the reward. Here we investigate the effects of the dopamine D2-like receptor antagonist raclopride (0, 25, 125, and 250 µg/kg) on the microstructure of licking for water and sodium chloride solutions (0.075 M, 0.15 M, and 0.3 M) in 12 h water-deprived rats. In each session, rats were exposed to brief contact tests (1 min) for each solution. Bout size, but not bout number, was decreased at the highest NaCl concentration. Raclopride reduced lick number owing to reduced bout size, while bout number was either not affected or even increased depending on the dose. These results are in agreement with the previous observations on sucrose licking, and suggest the involvement of dopamine D2-like receptors in an evaluation process occurring during the consummatory transaction with the reward.     

Dopamine applied into the nucleus accumbens and discriminative avoidance in rats

The actions of dopamine (DA) administered into the nucleus accumbens on motor function and discrimination were examined in rats trained to perform a discriminative conditioned avoidance response (DCAR). α-Methyl-p-tyrosine was found to suppress performance of the CAR although it did not impair discrimination. The administration of DA reinstated CAR performance but it also increased discriminative errors. Multivariate comparisons suggested that both of these effects were closely related to the stimulation of intertrial crossings by DA.     

Chronic methylphenidate induces increased quinone production and subsequent depletion of the antioxidant glutathione in the striatum

BackgroundMethylphenidate (Ritalin®) is a psychostimulant used chronically to treat attention deficit hyperactivity disorder. Methylphenidate acts by preventing the reuptake of dopamine and norepinephrine, resulting in an increase in these neurotransmitters in the synaptic cleft. Excess dopamine can be autoxidized to a quinone that may lead to oxidative stress. The antioxidant, glutathione helps to protect the cell against quinones via conjugation reactions; however, depletion of glutathione may result from excess quinone formation. Chronic exposure to methylphenidate appears to sensitize dopaminergic neurons to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We hypothesized that oxidative stress caused by the autooxidation of the excess dopamine renders dopaminergic neurons within the nigrostriatal pathway to be more sensitive to MPTP.MethodsTo test this hypothesis, male mice received chronic low or high doses of MPH and were exposed to saline or MPTP following a 1-week washout. Quinone formation in the striatum was examined via dot blot, and striatal GSH was quantified using a glutathione assay.ResultsIndeed, quinone formation increased with increasing doses of methylphenidate. Additionally, methylphenidate dose-dependently resulted in a depletion of glutathione, which was further depleted following MPTP treatment.ConclusionsThus, the increased sensitivity of dopamine neurons to MPTP toxicity following chronic methylphenidate exposure may be due to quinone production and subsequent depletion of glutathione.     

新生儿使用多巴胺时静脉血管保护方法的探讨

目的 探讨新生儿在使用多巴胺药物治疗时的静脉血管保护方法.方法 提取2008年2月至2010年5月期间儿科病例资料60例,对静脉输液的治疗方法及护理方法进行分析,并与同期未进行相应血管保护方法60例进行对比.结果 60例新生儿在应用多巴胺静脉输注过程中,4例出现轻微不良反应.2例出现严重不良反应;对照组患者出现轻微不良反应8例,出现严重不良反应6例,两组不良反应经过治疗全部痊愈.结论 血管选择优化,均匀给药,控制给药时间及良好的固定措施,配合临床密切观察来预防不良反应,是预防和保护血管发生损害的工作重点.     

Differences in the stereotypy response but not the hypomotility response to apomorphine in the roman high and low avoiding strains of rats

Two experiments were carried out to investigate differences in the behavioural responses to high and low doses of apomorphine in two strains of rats selectively bred for high and low avoidance on a two-way active avoidance task: the Roman High and Low Avoiders. Significant strain differences were found in the stereotypy resulting from a high dose of apomorphine (2 mg/kg s.c.). In a second experiment no strain differences were, however, apparent for the hypomotility produced by low doses of the drug (0.05 mg/ kg s.c.). Pretreatment with a low dose of apomorphine had no effect on the stereotypy response when the animals were subsequently retested with the high dose. These results may indicate differential sensitivities of dopamine receptors in these strains.