Interactions between guanabenz and clonidine in their cardiovascular effects in the rat

In Sprague-Dawley rats anesthetized with pentobarbital sodium (40 mg/kg, i.p.), guanabenz and clonidine exhibited mutually interactive effects on the cardiovascular system. Pretreatment with either antihypertensive agent (5 or 10 micrograms/kg, i.v.) significantly potentiated both the degree and duration of the initial elevation in arterial pressure and cardiac contractility promoted by the other compound (10 micrograms/kg, i.v.). On the other hand, discernible antagonization existed mutually for their delayed hypotensive, as well as negative inotropic and chronotropic actions. Furthermore, these circulatory changes displayed comparable trends under parallel drug interaction schemes, as revealed by correlation coefficient evaluations. It is possible that guanabenz and clonidine may share a common mechanism(s) in their cardiovascular actions.     

Alpha-2 agonist-induced memory impairment is mediated by the alpha-2A-adrenoceptor subtype

The activation of alpha2-adrenoceptors has been reported to impair memory functions in both rats and humans. The alpha2-adrenoceptor subtype responsible for this detrimental effect is still unknown. The effect of the alpha2-agonists clonidine and guanabenz on memory processes, in dependence to the time of administration, was evaluated in the mouse passive avoidance test. Clonidine (0.02-0.2 mg kg(-1) i.p.) and guanabenz (0.1-0.3 mg kg(-1) i.p.) induced amnesia in a dose-dependent manner. From time-course experiments emerged that the impairment of memory function was detectable only when clonidine and guanabenz were administered 60 min before or immediately after the training test, respectively. This detrimental effect was prevented by pretreatment with the alpha2-antagonist yohimbine (1-3 mg kg(-1) i.p.) and by the alpha2A-antagonist BRL-44408 (0.3-1 mg kg(-1) i.p.). By contrast, the alpha(2B,C) antagonists ARC-239 (10 mg kg(-1) i.p.) and prazosin (1 mg kg(-1) i.p.) did not revert the amnesia induced by both clonidine and guanabenz. At the highest effective doses, clonidine and guanabenz were devoid of behavioral side-effects as well as maintained unaltered the motor coordination, as revealed by the rota-rod test. Furthermore, none of the compounds used modified the spontaneous motility as indicated by the Animex apparatus. These results indicate that clonidine and guanabenz impaired memory processes in a mouse passive avoidance paradigm through the selective activation of the alpha2A-adrenoceptor subtype.     

Concomitant hypotensive and antinociceptive effects of guanabenz in conscious rats: involvement of nucleus reticularis gigantocellularis

Subcutaneous administration of guanabenz (1, 2, 5, or 8 mg/kg) in conscious Sprague-Dawley rats exerted concomitant suppressive actions on systolic pressure (tail-cuff sphygmomanometric measurement) and pain responses (hot-plate algesio-metric assay) that varied both in degree (antinociception much greater than hypotension) and response pattern. Furthermore, both depressive effects were appreciably attenuated by bilateral lesions of the nucleus reticularis gigantocellularis in the medulla oblongata. It is speculated that separate subpopulations of neurons within this reticular nucleus may be involved in the expression of hypotension and antinociception by this amino-guanidine derivative.     

Low doses of prazosin potantiates the antinociceptive/analgesic effect of amitriptyline

In this study, we aimed to reveal the interaction between the tricyclic antidepressant amitriptyline and a1-adrenoceptor antagonist prazosin in mice by using an analgesiometric device hot-plate. Amitriptyline (10 mg/kg) has analgesic effect as expected. Neither of the prazosin doses (0.1, 0.2, 0.5, 1 mg/kg) displayed analgesic effect alone. The combination of lower doses of prazosin (0.1, 0.2, 0.5 mg/kg) with amitriptyline (10 mg/kg) potentiated the antinociceptive effect of this drug. However, the relatively higher dose of prazosin (1 mg/kg) did not effect amitriptyline analgesia. Thus we conclude that the antinociceptive effect of amitriptyline is potentiated by low doses of prazosin.     

Rat clonidine mydriasis model: imidazoline receptors are not involved

The clonidine mydriasis model in rats has been widely applied in preclinical research to characterize alpha(2)-adrenoceptor antagonistic properties of drugs. The present study was undertaken to pharmacologically determine if imidazoline I(1) receptors are also involved in this model system. Sigmoid dose-response curves for pupillary dilation were produced in pentobarbital anesthetized rats by intravenous administration of increasing doses of agonists (guanabenz for alpha(2)-adrenoceptors, clonidine for both alpha(2)-adrenoceptors and imidazoline I(1) receptors, and rilmenidine for imidazoline I(1) receptors). Two antagonists (RS 79948 for alpha(2)-adrenoceptors and efaroxan for imidazoline I(1) receptors) were used to antagonize the mydriasis elicited by those three agonists, with antagonistic potencies calculated. In additional experiments, we examined the effect of the selective imidazoline I(1) receptor antagonist, AGN 192403, on clonidine-induced mydriasis. The results showed that pupillary response curves elicited by guanabenz, clonidine and rilmenidine were competitively antagonized by both RS 79948 (0.03-1 mg/kg) and efaroxan (0.03-1 mg/kg) in a dose-related fashion. The potencies of either antagonist against the three agonists were not significantly different. AGN 192403 (5 mg/kg) did not significantly shift the clonidine mydriasis curve. These results suggest that imidazoline I(1) receptors are not functionally involved in the rat clonidine mydriasis model and support this in vivo system as a useful model for studies of alpha(2)-adrenoceptors.     

Mechanism of action of clonidine in the forced-swimming test in mice

Clonidine displays immobility-reducing effects in the mouse swimming model at doses (0.06-16 mg/kg IP) which decrease spontaneous motility. Tricyclic antidepressants evoke a similar dissociation in motor activity. The immobility-reducing effect of clonidine (1 mg/kg at 30 min pretesting) was reversed by yohimbine (4 mg/kg) but was unaffected by prazosin (2 mg/kg) or alpha-methyl-paratyrosine (100 mg/kg), and was enhanced by reserpine (2.5 mg/kg). Mediation by alpha-2 postjunctional receptors was thus suggested. However, two 5-HT receptor blockers--methysergide (2 mg/kg) and ketanserin (8 mg/kg)--increased this effect of clonidine whereas the non selective agonist 5-MeODMT (1 mg/kg) reduced clonidine action. Conversely, pretreatment with a subthreshold dose of clonidine (0.06 mg/kg at 45 min pretesting) made effective subthreshold doses of three 5-HT uptake inhibitors (citalopram 2 mg/kg, indalpine and fluvoxamine 4 mg/kg) and of the 5-HT1 receptor agonist 8-OH-DPAT (0.5 mg/kg). According to these data, the mouse swimming model would trigger functional relationships between central alpha-noradrenergic and serotonergic mechanisms.     

Dopamine receptor antagonists block the effect of Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) on the opiate form of footshock-induced analgesia

Previous studies have shown that some of CNS actions of an endogenous peptide Tyr-MIF-1, are mediated by dopamine (DA) receptors. To study the effect of DA receptor blockade on the antiopiate properties of Tyr-MIF-1, the opiate form of footshock-induced analgesia was elicited in the rat. The nociceptive responses were determined using the hot-plate test (52.5 degrees C). Intraperitoneal pre-treatment with haloperidol (500 micrograms/kg), SCH 23390 (150 micrograms/kg), or spiroperidol (150 micrograms/kg) potentiated the antinociceptive effect of the footshock and blocked the antagonistic action of Tyr-MIF-1 (200 micrograms/kg and 2.0 mg/kg). A dose of haloperidol too small to potentiate the antinociceptive effect of the footshock (100 micrograms/kg) was still able to block the action of Tyr-MIF-1 (200 micrograms/kg). The results suggest that activation of DA receptors mediates the antagonizing effect of Tyr-MIF-1 on the opiate form of footshock-induced analgesia in the rat.     

On the mechanism of cross-tolerance between morphine- and nicotine-induced antinociception: involvement of calcium channels

The present study focused on the evaluation of a mechanism of nicotine-induced antinociception and cross-tolerance to antinociceptive effects between nicotine and morphine in mice. The results indicate that, at a dose of 3 mg/kg, nicotine produced a significant antinociception in the hot-plate test. Additionally, the L-type voltage-dependent calcium channel antagonists, nimodipine, verapamil and diltiazem (5, 10 and 20 mg/kg), as well as an opioid receptor antagonist naloxone (0.5 and 1 mg/kg), dose-dependently attenuated this nicotine-induced antinociception. In a second series of experiments, mice were treated with morphine (25 and 50 mg/kg) once daily, for 3 days. On the 4th day, the antinociceptive response of morphine (10 mg/kg) and nicotine (3 mg/kg) was measured. Tolerance to the effects of both drugs was observed only in mice pretreated with the highest dose of morphine. Furthermore, the administration of nimodipine, diltiazem, flunarizine (10 and 20 mg/kg), but not of verapamil (10 and 20 mg/kg) nor mecamylamine (1 and 2 mg/kg) prior to morphine injections, prevented this cross-tolerance to the antinociceptive effects of morphine and nicotine. These findings support the hypothesis that similar opioid- and calcium-dependent mechanisms are involved in morphine- and nicotine-induced antinociception and in the development of cross-tolerance between these drugs.     

The effect of paracetamol on nociception and dynorphin A levels in the rat brain

Male Wistar rats were administered with naloxone (1 mg/kg i.p.) or MR 2266 (5 mg/kg i.p) 15 min before paracetamol (400 mg/kg i.p.) treatment and the pain threshold was evaluated. Rats were subjected to the hot-plate and formalin tests and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in the hypothalamus, hippocampus, striatum, brainstem, frontal and parietal-temporal cortex by radioimmunoassay. Pretreatment with naloxone abolished paracetamol antinociceptive activity both in hot-plate and in the first phase, but not in the second phase of the formalin test, while MR 2266 pretreatment was able to antagonise paracetamol effect either in the hot-plate test or in both phases of the formalin test. Among different brain areas investigated paracetamol significantly decreased ir-dynorphin A levels only in the frontal cortex. MR 2266 but not naloxone reversed the decrease in ir-dynorphin A levels elicited by paracetamol. Paracetamol seems to exert its antinociceptive effect also through the opioidergic system modulating dynorphin release in the central nervous system (CNS) of the rat, as suggested by the decrease in the peptide levels.     

Alpha2 adrenoceptors modulate the nociceptive jaw-opening reflex in rats

The jaw-opening reflex in lightly anesthetized rats induced by intrapulpal (left maxillary) electrical tooth pulp stimulation and quantified by the electromyograms (threshold values) recorded from the ipsilateral digastric muscle was used as the experimental pain index. The threshold for the jaw-opening reflex was significantly elevated by clonidine (12.5 to 50 micrograms/kg, i.v.) and was inversely correlated with the frequency of stimulation. The analgesia elicited by clonidine was antagonized by pretreatment with the alpha 2-adrenoceptor antagonist yohimbine (1 mg/kg, i.v.). All doses of clonidine produced an initial transient pressor response followed by a sustained hypotension and bradycardia. However, there was no direct correlation between the antinociceptive and cardiovascular effects of clonidine. It is proposed that clonidine modulates jaw-opening reflex analgesia by specifically activating alpha 2-adrenoceptors.     

alpha2-Adrenergic agonists antagonise the anxiolytic-like effect of antidepressants in the four-plate test in mice

Selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs) has been reported to be efficient in anxiety disorders. Some animal models have demonstrated an anxiolytic-like effect following acute administration, however, it is not yet known how noradrenergic receptors are implicated in the therapeutic effects of antidepressants (ADs) in anxiety. The effects of two alpha(2)-adrenoceptor agonists (clonidine, guanabenz) on anxiolytic-like effect of two SSRIs (paroxetine and citalopram) and two SNRIs (venlafaxine and milnacipran) were evaluated in the four-plate test (FPT) in mice. Paroxetine (4 mg/kg), citalopram (8 mg/kg), venlafaxine (8 mg/kg), and milnacipran (8 mg/kg) administered intraperitoneally (i.p.) increased the number of punishments accepted by mice in the FPT. Clonidine (0.0039-0.5 mg/kg) and guanabenz (0.03-0.5mg/kg) had no effect on the number of punishments accepted by mice. Clonidine (0.03 and 0.06 mg/kg) and guanabenz (0.125 and 0.5 mg/kg) (i.p. -45 min) reversed the anti-punishment effect of paroxetine, citalopram, venlafaxine and milnacipran (i.p. -30 min). But if the antidepressants are administered 45 min before the test and alpha(2)-adrenoceptor agonists 30 min before the test, alpha(2)-adrenoceptor agonists failed to alter the anti-punishment effect of antidepressants. The results of this present study indicate that alpha(2)-adrenoceptor agonists antagonise the anxiolytic-like effect of antidepressants in mice when they are administered 15 min before the administration of antidepressant suggesting a close inter-regulation between noradrenergic and serotoninergic system in the mechanism of SSRIs and SNRIs in anxiety-like behaviour.     

泰国眼镜蛇毒cobratoxin的化学修饰物receptin的镇痛作用

目的 在动物疼痛模型上,观察泰国眼镜蛇长链突触后α-神经毒素cobratoxin（CTX）的化学修饰物receptin（REC）的镇痛作用及其阿托品和纳洛酮对其镇痛作用的影响。方法 采用腹腔注射（i．p．,5mg/kg,7．07mg/kg,10mg/kg）或脑室注射（i．c.v．,62．5g/kg）的方法给予REC;采用小鼠热板反应、扭体反应及大鼠甩尾反应试验研究药物的镇痛作用;应用预先给予阿托（atropine,Atr;0．5mg／kg,i．m．或10mg／kg,i．p．）或纳洛酮（naloxone,Nal;3mg／kg,i．p．）研究胆碱能及阿片肽能神经在REC镇痛中的作用;采用mnilnex试验观察REC对小鼠自发活动的影响。结果 REC（5mg／kg,7．07mg/kg及10mg/kg,i．p．）在小鼠热板试验及扭体试验中均呈现出剂量依赖性镇痛作用,并于给药后20小时出现显著镇痛作用。在大鼠甩尾试验中,REC62．5mg/kg（相当于全身给药的1／160,i．c.v．）后产生显著镇痛作用。阿托品或纳洛酮不能阻断REC的镇痛作用。高剂量REC（10mg／kg,i．p．）对小鼠的自发活动无明显影响。结论 REC具有镇痛作用,尽管中枢神经系统参与REC的镇痛作用,但外周神经系统可能亦介导REC的镇痛作用。中枢胆碱能及阿片肽能神经系统可能不参与REC的镇痛作用。     

Uliginosin B presents antinociceptive effect mediated by dopaminergic and opioid systems in mice

Previous studies have shown that uliginosin B inhibits dopamine reuptake in rat brain. This compound occurs in Hypericum polyanthemum and H. caprifoliatum for which was reported to have antinociceptive effect sensitive to naloxone. The aim of this study was to assess the antinociceptive effect of uliginosin B and to evaluate the involvement of opioid and dopaminergic receptors activation. Uliginosin B presented antinociceptive effect in hot-plate and abdominal writhing tests, in mice, at doses that did not impair the motor coordination (15 mg/kg, i.p.). Uliginosin B in high dose (90 mg/kg, i.p.) presented ataxic effect in the rotarod apparatus. These effects seem to be mediated by distinct receptors since the effect on the hot-plate was completely abolished by naloxone and sulpiride, but it was unaffected by SCH 23390. On the other hand, the motor impairment induced by uliginosin B was completely prevented by naloxone and partially prevented by sulpiride and SCH 23390. However, the receptors' activation appears to be indirect since uliginosin B did not bind to opioid and dopaminergic receptors. Thus, uliginosin B effects probably are due to its ability to inhibit monoamine reuptake with consequent activation of dopamine receptors and indirect stimulation of opioid system.     

Antinociceptive effect of ketanserin in mice: involvement of supraspinal 5-HT2 receptors in nociceptive transmission.

The involvement of 5-HT2 receptors in pain transmission was investigated in mice. Subcutaneous administration of the selective 5-HT2 receptor antagonist ketanserin produced dose-dependent antinociception in the hot-plate and acetic acid-induced writhing tests with ED50 values (95% confidence limit) of 1.51 (1.13-1.89) and 0.62 (0.10-1.40) mg/kg, respectively, but was without any significant effect on the tail-flick test. Pretreatment with the catecholamine depletors 6-hydroxydopamine (2.5 micrograms, i.c.v.) or alpha-methyl-p-tyrosine (200 mg/kg, s.c.), or the serotonin synthesis inhibitor p-chlorophenylalanine methylester (200 mg/kg, s.c.), resulted in a significant decrease in the antinociceptive effect of ketanserin. Likewise, intrathecal (i.t.) administration of 1 microgram/mouse of idazoxan (an alpha 2-antagonist), methysergide (mixed 5-HT1, and 5-HT2 antagonist) or ketanserin also reversed the antinociceptive effect of s.c. administered ketanserin. The results of this work indicate that 5-HT2 receptors located supraspinally may inhibit descending nociceptive neurotransmission. In addition, these studies suggest that 5-HT2 receptors located at the spinal level modulate nociception.     

Locus coeruleus lesions in the rat enhance the antinociceptive potency of centrally administered clonidine but not morphine

The nucleus locus coeruleus (LC) has been implicated in the descending inhibition of spinal nociceptive dorsal horn neurons, spinal nociceptive reflexes and in the antinociception produced by morphine. To further explore the involvement of the LC in antinociception, bilateral electrolytic lesions in the LC were made in adult male Sprague-Dawley rats. Lesions in the LC did not alter the antinociception produced by morphine (2.5 and 5 micrograms) administered in the periaqueductal gray in either the tail-flick (TF) or hot-plate (HP) tests when tested 7 and 14 days after the lesions. Baseline nociceptive thresholds in the TF and HP tests likewise were not affected at 7 or 14 days post-lesion. In contrast, the antinociceptive potency of clonidine administered intrathecally on day 13 post-lesion was enhanced significantly in the TF test; the antinociceptive ED50 of the LC lesion group was 0.52 micrograms whereas that of the sham lesion group was 2.29 micrograms. The antinociceptive potency of clonidine administered systemically (750 and 500 micrograms/kg, s.c.) was also enhanced in the LC lesion group in the TF but not the HP test. Norepinephrine (NE) in the lumbar spinal cord was correlated negatively and significantly with the extent of destruction of the LC. The lumbar spinal content of NE was reduced maximally at 12 days post-lesion (to 56% of control). The binding of [3H]clonidine in the lumbar spinal cord was slightly greater in the LC lesion than sham lesion group; the Bmax values were 42.4 fmol/mg protein and 35.5 fmol/mg protein for the LC lesion and sham lesion groups, respectively. It is suggested that the LC participates in the descending inhibition of spinal nociceptive transmission and that this inhibition may be mediated in the spinal cord by alpha-2 adrenoceptors located postsynaptically with respect to the NE terminals of the spinopetal LC efferents.     

Mechanisms by which the putative serotonin receptor antagonist metitepin alters nociception in mice

Summary The putative serotonin (5-HT) receptor antagonist metitepin (0.5 mg/ kg, intraperitoneally) produced hypoalgesia in the increasing temperature hot-plate test and hyperalgesia in the tail-flick test in mice. The effects of metitepin were not altered after depletion of 5-HT by the neurotoxin 5,7-dihydroxytryptamine (5, 7-DHT, 80 g free base, intracerebroventricularly) or the serotonin synthesis inhibitor p-chlorophenylalanine (PCPA, 400 mg/kg for 10 consecutive days). After chronic administration (2 or 5 mg/kg for 18 consecutive days) tolerance to the effect of metitepin (0.5 mg/kg) and cross-tolerance to the antinociceptive effect of the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 3 mg/kg) was found in the hot-plate test but not in the tail-flick test. It is suggested that metitepin may block descending 5-HT transmission while more complex mechanisms of action are involved at supraspinal level. One possibility is that metitepin exhibits partial agonist properties or, alternatively, that the drug may block 5-HT subsystems which tonically enhance nociception.     

XAMI and DCDM, agonists at cAMP-associated octopamine receptors in cockroach nerve cord, produce centrally mediated antinociception in mice.

The ability of XAMI (2,3-xylylaminomethyl-2'-imidazoline), the most potent agonist of cAMP-associated octopamine-sensitive adenylate cyclase in cockroach (Periplaneta americana) nerve cord yet reported, and DCDM (N-demethylchlordimeform), a partial octopamine agonist in this preparation, to produce centrally mediated antinociception in mice was evaluated. The antinociception produced by these compounds was compared to that previously reported for p-octopamine, a phenylethylamine and endogenous mammalian hydroxyphenolic analog of norepinephrine. Consonant with the reported greater agonistic activity of XAMI on octopamine-sensitive adenylate cyclase, XAMI was more potent than p-octopamine by spinal or supraspinal administration in the abdominal constriction test (E50 = 0.013 micrograms i.t., 1.45 micrograms i.c.v.) and in the 48 degrees C hot-plate test (ED50 = 0.06 micrograms i.t., 0.4 micrograms i.c.v.), but was inactive in the tail-flick test (up to 4.0 micrograms i.c.v. or i.t.). Unlike p-octopamine, both XAMI and DCDM were active by peripheral routes of administration. DCDM was orally active in the mouse acetylcholine-induced abdominal constriction test (ED50 = 9.98 mg/kg p.o.) and was active via the s.c. route in this test (ED50 = 2.36 mg/kg), the 48 degrees C hot-plate test (ED50 = 5.40 mg/kg) and the tail-flick test (ED50 between 15 and 30 mg/kg). It appeared to be a full agonist against these endpoints. XAMI produced dose-related antinociception in the abdominal constriction test (ED50 = 0.10 mg/kg s.c.) and in the 48 degrees C hot-plate test (ED50 = 3.71 mg/kg p.o. and 0.46 mg/kg s.c.), where the antinociceptive response persisted for at least 60 min following subcutaneous or oral administration. Both compounds were less potent via peripheral routes than clonidine (as reference) in these tests. Mechanistically, XAMI-induced antinociception was antagonized by yohimbine and idazoxan, but not the opiate antagonist naloxone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mutual potentiation of antinociceptive effects of morphine and clonidine on motor and sensory responses in rat spinal cord

Clonidine and morphine depress nociceptive reflex responses when given alone; when given in combination, the effect of each is potentiated by the other. The present study was designed to test if activity in ascending axons evoked by electrical stimulation of afferent C-fibers in the sural nerve of the rat also exhibits potentiation of the depressant effects of clonidine and morphine when both drugs are administered in combination by intrathecal (i.t.) injection to the lumbar spinal cord. For comparison, experiments were also carried out on the tail-flick response in rats. The results show that clonidine produced a dose-dependent inhibition of the tail-flick response (Ed50 20 micrograms); a combination of ineffective doses of clonidine (0.3 microgram) and morphine (2 micrograms) significantly inhibited the tail-flick response; clonidine (35 micrograms) reduced spontaneous, C-fiber-evoked and, due to co-activation, A delta-fibre-evoked activity in ascending axons; and clonidine at a threshold (0.3 microgram) or higher (3 micrograms) dose administered together with morphine at a dose (2 micrograms) that caused only a moderate inhibition produced a supra-additive effect in significantly depressing spontaneous. A delta- and C-fiber-evoked ascending activity. The dose-response curve of depression by morphine alone of C-fiber-evoked activity (ED50 8 micrograms) is significantly shifted by clonidine to the left (ED50 0.9 microgram). Naloxone (0.2 mg/kg) injected intravenously did not affect the inhibition of ascending activity caused by clonidine at the highest dose (35 micrograms), but it reduced the depressant effect of combined i.t. administration of clonidine and morphine. The potentiation of the antinociceptive effects of clonidine and morphine given in combination are possibly due to actions of the two drugs at different sites between the nociceptive afferents and the neurons sending their axons to the brain.     

A short-chain α-neurotoxin from Naja naja atra produces potent cholinergic-dependent analgesia

Objective To investigate the analgesia induced by cobrotoxin （CT） from venom of Naja naja atra, and the effects of atropine and naloxone on the antinociceptive activity of CT in rodent pain models. Methods CT was administered intraperitoneally （33.3, 50, 75 μg/kg）, intra-cerebral venticularly （2.4 μg/kg） or microinjected into periaqueductal gray （PAG, 1.2 μg/kg）. The antinociceptive action was tested using the hot-plate test and the acetic acid writhing test in mice and rats. The involvement of cholinergic system and the opioid system in CT-induced analgesia was examined by pretreatment of animals with atropine （0.5 mg/kg, im or 10 mg/kg, ip） or naloxone （3 mg/kg, ip）. The effect of CT on motor activity was tested using the Animex test. Results CT （33.3, 50 and 75 μg/kg, ip） exhibited a dosedependent analgesic action in mice as determined with hot-plate test and acetic acid writhing test. In the mouse acetic acid writhing test, the intra-cerebral ventricle administration of CT 2.4 μg/kg （1/23th of a systemic dose） produced marked analgesic effects. Microinjection of CT 1.2 μg/kg （1/46th of systemic dose） into the PAG also elicited a robust analgesic action in the hot-plate test in rats. Atropine at 0.5 mg/kg （ira） or naloxone at 3 mg/kg （ip） failed to block the analgesic effects of CT, but atropine at 10 mg/kg （ip） did antagonize the analgesia mediated by CT in the mouse acetic acid writhing test. At the highest effective dose of antinociception （75 μg/kg）, CT did not change the spontaneous mobility of mice. Conclusion These results suggest that CT from Naja naja atra venom has analgesic effects. Central nervous system may be involved in CT＇ analgesic effects and the PAG may be the primary central site where CT exerts its effects. The central cholinergic system but not opioid system appears to be involved in the antinociceptive action of CT.     

Non-adrenergic exploratory behavior induced by moxonidine at mildly hypotensive doses

Moxonidine is a centrally-active imidazoline compound with preferential affinity for imidazoline receptors (IR) over alpha(2)-adrenoceptors (alpha(2)AR). Clinically, moxonidine has proven advantageous for treating hypertension over pure alpha(2)-adrenergic agonists (i.e., guanabenz) due to its lowered incidence of sedative side effects. The present experiments reveal divergent behavioral effects of low doses of moxonidine and guanabenz in C57Bl/6 mice in an exploratory arena. Low-dose moxonidine (0.05 mg kg(-1) i.p.) elicited an increase in novel object contacts (+36%) and more movement into central space (+56%; P<0.01) compared to saline-injected controls; whereas guanabenz induced only dose-responsive sedative-like behaviors in the same paradigm. Yet, the two agonists were indistinguishable in terms of blood pressure changes over a similar dose range (0.025-0.1 mg kg(-1) i.p.) in consciously free-moving mice (Delta mean+/-S.E.M.=-12.3+/-3.2 mm Hg for moxonidine versus -13.5+/-1.9 mm Hg for guanabenz). As expected of alpha(2)AR involvement, the sedative-like effects of guanabenz were completely blocked by pretreatment with the non-imidazoline alpha(2)AR-antagonist, SKF86466 (0.5 or 1.0 mg kg(-1) i.p.). However, the pro-exploratory effects of low doses of moxonidine (0.05 or 0.1 mg kg(-1)) were not antagonized by SKF86466. These results suggest that moxonidine acts preferentially through a non-adrenergic mechanism, possibly IR-mediated, to elicit pro-exploratory behavior.