Antidepressants enhance the antinociceptive effects of carbamazepine in the acetic acid-induced writhing test in mice

Some antidepressants, as well as antiepileptics, are effective for treating pain of varying etiology. The present study was designed to characterize the antinociceptive effects of imipramine, a tricyclic antidepressant, fluvoxamine, a selective serotonin reuptake inhibitor, milnacipran, a serotonin noradrenaline reuptake inhibitor, and carbamazepine, an antiepileptic drug, using the acetic acid-induced writhing test in mice. Imipramine (1.25–10 mg/kg, i.p.), fluvoxamine (5–40 mg/kg, i.p.) and milnacipran (2.5–20 mg/kg, i.p.) all dose-dependently and significantly reduced the number of writhes induced by the injection of acetic acid (0.8% (v/v)), although the maximal effect of milnacipran was weaker than those of imipramine and fluvoxamine. Similarly, carbamazepine (5–20 mg/kg, i.p.) also showed a dose-dependent and significant antinociceptive effect. In combination studies, the co-administration of a sub-effective dose of carbamazepine (5 mg/kg, i.p.) with imipramine (1.25 and 2.5 mg/kg, i.p.), fluvoxamine (10 mg/kg, i.p.) or milnacipran (1.25 and 2.5 mg/kg, i.p.) significantly reduced the number of writhes. Additionally, the hole-board test revealed that the medications with significant antinociceptive effects barely produced changes in motor activity that could possibly affect writhing behavior. Thus, the present study demonstrated that the antinociceptive effect of carbamazepine is enhanced by combination with imipramine, fluvoxamine and milnacipran. Therefore, the combined therapy using antidepressants and carbamazepine may be useful clinically for the control of pain.     

The blockade of bulbospinal inhibition by imipramine, desipramine and pargyline

Bulbospinal inhibition of the spinal cord monosynaptic reflex was antagonized by im-ipramine HCl (5 $\text{mg}\text{kg}$), desipramine HCl (4.8 $\text{mg}\text{kg}$) and pargyline HCl (30.0 $\text{mg}\text{kg}$) in unanaesthetized, decerebrate cats. The blocking action of imipramine was prevented in animals pretreated for three consecutive days with dl-p-chlorophenylalanine (300 $\text{mg}\text{kg}$) but not in animals pretreated with dl-α-methyl-p-tyrosine methyl ester HCl (125 $\text{mg}\text{kg}$) 16 and 4 hr prior to recording. These results do not support the proposal of Clineschmidt and Anderson (1970) that the bulbospinal inhibitory pathway contains a 5-hydroxytryptamine (5-HT) link. Rather, the findings suggest that 5-HT is involved in antagonizing bulbospinal inhibition of the monosynaptic reflex.     

Effect of imipramine and desipramine on the metabolism of serotonin in midbrain raphe stimulated rats

Imipramine, 5 mg/kg, i.p., completely blocked the forebrain 5-HIAA increase in rats that have undergone midbrain raphe stimulation whereas desipramine, 5 mg/kg, i.p., did not. This finding is compatible with the hypothesis that imipramine can block selectively the membrane uptake of serotonin in the central serotoninergic neurons.     

Evidence that imipramine activates 5-HT1C receptor function.

The anti-immobility effect of imipramine (15 mg/kg) in the forced swimming test in mice was antagonized by the non-selective 5-hydroxytryptamine (5-HT) antagonist, metitepine (0.5 mg/kg), by the 5-HT1C/5-HT2 antagonist, mesulergine (15 mg/kg), and by the dopamine D2 antagonist, d,l-sulpiride (50 mg/kg). These three antagonists did not alter the behaviour of imipramine-treated mice in an open-field and did not reduce imipramine brain levels. The 5-HT2 antagonist, ritanserin (0.06 mg/kg), the 5-HT1A/5-HTB antagonist, l-propranolol (20 mg/kg), and the 5-HT3 antagonists, endo-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-oxo-1H- benzimidazole-1-carboxamide hydrochloride (DAU 6215; 0.1 mg/kg) and 1,2,3,9-tetrahydro-9-methyl-3[(2-methyl-1H-imidazol-1-yl)methyl]-4H- carbazol-4-one, HCl.2H2O) (GR 38032F; 0.1 mg/kg), failed to reduce imipramine-induced anti-immobility. Subthreshold doses of 8-hydroxy-2-(di-n-propylamino)tetralin hydrochloride (8-OH-DPAT; 0.5 mg/kg) and imipramine (7.5 mg/kg) did not synergize in reducing immobility. d,l-Sulpiride, but not mesulergine, antagonized the effect of desipramine (15 mg/kg) in the forced swimming test. All compounds were administered i.p. 6 min before imipramine or desipramine, given i.p. 30 min before the testing. Imipramine produced 50% inhibition of [3H]mesulergine binding to 5-HT1C receptors at 10 microM, a concentration below that obtained following i.p. imipramine administration. The results suggest a contribution of 5-HT1C receptors in the mechanism of the imipramine effect in the forced swimming test.     

Opposing central autonomic actions of alpha 1- and alpha 2-adrenoceptor antagonists on oculomotor tone

Electrical stimulation of the afferent sciatic nerve produces reflex mydriasis in anesthetized rats. The alpha 2-antagonist idazoxan (10-100 micrograms/kg i.v.) inhibited this reflex in a dose-dependent fashion. In contrast, the alpha 1-antagonist prazosin (30-300 micrograms/kg i.v.), produced a dose-related enhancement of the reflex. Single dose administration of the alpha 2-antagonists yohimbine (3.0 mg/kg i.v.), rauwolscine (3.0 mg/kg i.v.) and idazoxan (1.0 mg/kg) also blocked the reflex, whereas the alpha 1-antagonists phenoxybenzamine (3.0 mg/kg i.v.), corynanthine (1.0 mg/kg i.v.) and prazosin (1.0 mg/kg i.v.) potentiated this response. These studies demonstrate that alpha 2-antagonists block and alpha 1-adrenoceptor antagonists potentiate alpha 2-adrenoceptor-mediated inhibition of oculomotor tone.     

Mode of inhibitory action of propiverine hydrochloride on the micturition movements of the bladder in dogs

Propiverine hydrochloride (P-4) is a new derivative of benzilic acid. The effect of P-4 on the vesico-detrusor reflex (corresponding to the first reflex of Barrington) in anesthetized or decerebrated dogs was studied to elucidate the mode of action of the drug. When bladder contraction was induced by electrical stimulation of the distal ending of the pelvic nerve under the bilateral pelvic nerve and hypogastric nerve transection, P-4 (2, 5 and 10 mg/kg, i.v.) significantly inhibited the contraction. A similar effect was also observed following intravenous administration of flavoxate (10 and 20 mg/kg), verapamil (1 mg/kg) or propantheline (2 mg/kg), while thiopental (4 mg/kg, i.v.) had no significant effect. When the bladder was filled under the bilateral pelvic nerve and hypogastric nerve transection, an increase of afferent impulses from the distal ending of a pelvic vesical branch was observed. P-4 (10 mg/kg, i.v.) had no effect on the afferent impulses. When the central endings of the pelvic vesical branches were electrically stimulated, reflex discharges were noted from a pelvic vesical branch on the contralateral side. Thiopental (2 and 4 mg/kg, i.v.) markedly decreased the reflex discharge, whereas P-4 (10 mg/kg, i.v.) caused no such inhibition. These findings suggest that the inhibition of the vesico-detrusor reflex by P-4 may result from its inhibitory action on the efferent terminal of the pelvic nerve.     

Analysis of the action of CNS depressant drugs on somato-somatic reflexes in the cat.

The effects of diazepam (0·01–0·1 mg/kg, i.v.) diphenylhydantoin (DPH) (10–40 mg/kg, i.v.) phenobarbital (5–40 mg/kg, i.v.) and chlorpromazine (0·5–2·0 mg/kg, i.v.) were compared in the chloralose-anaesthetized cat. Responses were studied to stimulation of hindlimb muscle extensor and flexor afferents, and hind- and forelimb cutaneous afferents. In this preparation, stimulation of hindlimb afferents produced an initial short latency segmental spinal discharge (monosynaptic and polysynaptic potentials) followed by a longer latency supraspinal reflex. Forelimb cutaneous afferent stimulation produced only a supraspinal discharge. All segmental reflexes studied were depressed moderately by diazepam and DPH and more strongly by phenobarbital and chlorpromazine. Unlike diazepam, the low dose of DPH often augmented some of these reflexes. All supraspinal reflexes examined were completely blocked by diazepam and phenobarbital, whereas they were merely reduced, but never completely inhibited, by chlorpromazine. Diphenylhydantoin had a mixed effect: spino-bulbo-spinal reflexes evoked by hindlimb muscle afferents were blocked, whereas the response to forelimb cutaneous afferents was particularly resistant to DPH. Decerebellation did not prevent the inhibition of the supraspinal reflex by the various drugs. It is concluded that the four compounds exhibit a different profile in regard to their effect on somato-somatic reflexes.     

Mechanisms of spinal reflex depressant effects of CS-722, a newly synthesized centrally acting muscle relaxant, in spinal rats.

The mechanisms of the depressant action of (R)-4-chloro-2-(2-hydroxy-3-morpholinopropyl)-5-phenyl-4-isoxaz olin-3-one hydrochloride (CS-722), a newly synthesized centrally acting muscle relaxant, on spinal reflexes were investigated in spinal rats. The drug CS-722 (50 mg/kg, i.v.) depressed the polysynaptic reflex but was less effective on the monosynaptic reflex. Eperisone-HCl (10 mg/kg, i.v.) and baclofen (2 mg/kg, i.v.) markedly decreased the monosynaptic and polysynaptic reflexes, with longer durations than CS-722; CS-722, eperisone and baclofen depressed the dorsal root reflex. The excitability of the motoneurone was reduced by CS-722 and eperisone. Excitability of the primary afferent fibres was reduced by CS-722, while eperisone and baclofen had no effect. Both CS-722 and eperisone did not have a depressant influence on the focal synaptic potential. These results suggest that CS-722 and eperisone but not baclofen, have a common motoneurone-membrane-stabilizing action and that this action may contribute, in part, to the spinal reflex depressant effects of CS-722 and eperisone.     

Interaction of morphine and naloxone in acute spinal cats

Naloxone (0.2 mg/kg i.v.) increased both monosynaptic and polysynaptic reflex amplitudes in acute spinal cats. The increase in monosynaptic reflex amplitude was greater than that for polysynaptic reflexes. Morphine administered intravenously. 36 min following naloxone, depressed monosynaptic reflexes at 3 and 12 mg/kg, and polysynaptic reflexes at 12 mg/kg. A subsequent 0.2 mg/kg dose of naloxone was administered 54 min after beginning the morphine injection. The action of naloxone on polysynaptic reflexes was enhanced by intervening morphine; that on monosynaptic reflexes was not. The actions of morphine and naloxone in these studies do not appear to involve cholinergic synapses in the spinal cord.     

Serotonergic mechanism in imipramine induced antinociception in rat tail flick test

Substantial evidence has accumulated that spinally projecting serotonergic neurons modulate nociception. However, the exact receptor subtypes that mediate the antinociceptive response of serotonin within the spinal cord continue to be a subject of debate. Therefore, we explored the effect of serotonergic system on imipramine induced antinociception by using 5-Hydroxytryptamine-3 (5HT3) receptor antagonist ondansetron and 5-Hydroxytryptamine-2 (5HT2) receptor antagonist mianserine, and depletion of brain 5-Hydroxytryptamine (5HT) with p-chlorophenyl alanine (PCPA). Male wistar strain rats were pretreated with either ondansetron (0.5 mg/kg, i.p.) or mianserine (1 mg/kg, i.p.). After 15 minutes, rats received injection of imipramine (10 mg/kg). Nociception was assessed by tail-flick method. Imipramine (2 mg, 5 mg, 10 mg, and 20 mg/kg) produce antinociceptive response in the dose dependent manner. Prior treatment with 5HT3 antagonist, Ondansetron and 5HT2 antagonist, mianserine reduce the antinociceptive response of imipramine. In PCPA treated rats imipramine (10 mg/kg) failed to produce antinociception. These results indicate that the 5HT plays an important role in imipramine induced antinociception.     

Exacerbation of harmaline-induced tremor by imipramine

Imipramine is a well-established tricyclic antidepressant which was first approved for the treatment of depression in the late fifties. Antidepressant effect of imipramine is attributed to inhibition of serotonin (5HT) and noradrenaline (NA) reuptake in brain. These monoamines have been implicated in a variety of neurological disorders including tremor. In the present investigation attempt was made to study the effect of imipramine on harmaline-induced tremor in rats. Male Sprague Dawley rats weighing 115+/-2.5 g were given harmaline (10 mg/kg, i.p.) alone or along with imipramine (30 min before harmaline) in doses of 60 and 90 mg/kg respectively. The latency of onset, intensity and duration of tremor and EMG were recorded. To substantiate the role of 5HT in aetiopathology of tremor the above experiment was repeated in the rats pretreated with P-chlorophenylalanine (PCPA), a potent 5HT depleter. The levels of 5HT and 5-hydroxyindole acetic acid (5HIAA) in the brain stem were measured using high performance liquid chromatography. Imipramine dose-dependently exacerbated the duration, intensity and amplitude of EMG following harmaline-induced tremor. Imipramine treatment further decreased harmaline-induced 5HT turnover in the brain stem. However, this was statistically insignificant. Depletion of 5HT produced a significant reduction in the intensity and duration of harmaline-induced tremor. In conclusion, this study suggests that imipramine exacerbates harmaline-induced tremor. Clinical use of imipramine for the treatment of depression in patients who also suffer from tremors may require a close monitoring.     

Pharmacokinetics and metabolism of thioridazine during co-administration of tricyclic antidepressants

1. Because of serious side-effects of thioridazine and tricyclic antidepressants (cardiotoxicity), a possible influence of imipramine and amitriptyline on the pharmacokinetics and metabolism of thioridazine was investigated in a steady state (2-week treatment) in rats. 2. Imipramine and amitriptyline (5 and 10 mg kg(-1) i.p., respectively) elevated 30 and 20 fold, respectively, the concentration of thioridazine (10 mg kg(-1) i.p.) and its metabolites (N-desmethylthioridazine, 2-sulphoxide, 2-sulphone, 5-sulphoxide) in blood plasma. Similar, yet weaker increases in the thioridazine concentration were found in the brain. Moreover, an elevation of thioridazine/metabolite ratios was observed. 3. Imipramine and amitriptyline added to control liver microsomes in vitro inhibited the metabolism of thioridazine via N-demethylation (an increase in K(m)), mono-2-sulphoxidation (an increase in K(m) and a decrease in V(max)) and 5-sulphoxidation (mainly a decrease in V(max)). Amitriptyline was a more potent inhibitor than imipramine of the thioridazine metabolism. 4. The varying concentration ratios of antidepressant/thioridazine in vivo appear to be more important to the final result of the pharmacokinetic interactions than are relative direct inhibitory effects of the antidepressants on thioridazine metabolism observed in vitro. 5. Besides direct inhibition of the thioridazine metabolism, the decreased activity of cytochrome P-450 towards 5-sulphoxidation, produced by chronic joint administration of thioridazine and the antidepressants, seems to be relevant to the observed in vivo interaction. 6. The obtained results may also point to inhibition of another, not yet investigated, metabolic pathway of thioridazine, which may be inferred from the simultaneous elevation of concentrations of both thioridazine and the measured metabolites.     

Morphine and meperidine on bulbospinal inhibition of the monosynaptic reflex

The effects of morphine and meperidine were studied on the ventromedial bulbospinal inhibition of the monosynaptic reflex (MRS) in decerebrate unanesthetized cats. Administration of these agents in accumulative doses (0.5–16 mg/kg, i.v.) progressively blocked this inhibition. Meperidine was more potent in blocking this inhibition when administered by close-arterial injection to the spinal cord than when administered i.v. which suggests that the spinal cord is a major site of action. The results of this study are contrary to the suggestion made by Takagi et al. (1955), that these drugs enhance bulbospinal inhibition of the MSR.     

Amphetamine-induced inhibition of tyrosine hydroxylation in homogenates of rat corpus striatum.

Tyrosine hydroxylase activity was measured in vitro by following the rate of production of ¹⁴CO₂ from [¹⁴C]-DOPA newly formed from L-[1-¹⁴C]-tyrosine in a crude synaptosomal preparation of striatal homogenates which contained only endogenous pteridine cofactor. Administration of (+)-amphetamine in vivo (0·50–5·0 mg/kg, i.p.) led to a specific local inhibition of tyrosine hydroxylase activity, after a 15–30 min delay and persisted for at least 4 hr (50% inhibition at 2·5 mg/kg), in nerve endings prepared from the corpus striatum of the rat brain. (?)-Amphetamine was less potent (25% inhibition at 5 mg/kg). There was no change in the level of tyrosine hydroxylase in cell-free extracts and no inhibition of substrate-uptake into nerve endings or change in the level of endogenous tyrosine. When striatal nerve endings were exposed directly to amphetamine in vitro (10 μM), stimulation rather than inhibition of tyrosine hydroxylation occurred, although the hydroxylated metabolites p-hydroxyamphetamine and p-hydroxynorephedrine inhibited the reaction (at 0·1–10 μM). Nevertheless, the inhibitory effect of (+)-amphetamine in vivo persisted in the rat after blockade of microsomal oxidases with SKF-525A (40 mg/kg, i.p.) as well as in the guinea pig, a species in which amphetamine is weakly p-hydroxylated. Interruption of impulse flow in the nigro-striatal pathway by electrothermic lesions was found to decrease tyrosine hydroxylase activity in the striatum, possibly as a result of an increased intraneuronal accumulation of dopamine which could enhance the end-product feedback inhibition of tyrosine hydroxylase. Inhibitory effects of in vivo administration of amphetamine on tyrosine hydroxylase activity in striatal synaptosomes may similarly be mediated by a decreased impulse flow in striatal dopamine neurones. The inhibitory effect of (+)-amphetamine (5 mg/kg, i.p.) was interrupted by blockade of striatal dopamine-receptors with chlorpromazine (10 mg/kg, i.p.) and by blockers of γ-aminobutyric acid-receptors (bicuculline or picrotoxin, 2·5 mg/kg, i.p.). Local striatal receptors of dopamine may thus be involved in this action of amphetamine or descending γ-aminobutyric acid-neurones may mediate a neurophysilogical feedback regulation of activity in the nigro-striatal pathway.     

2-phenylethylamine and methamphetamine enhance the spinal monosynaptic reflex by releasing noradrenaline from the terminals of descending fibers.

Experiments were performed on spinalized rats transected at C1. Intravenous administration of 2-phenylethylamine-HCl (PEA-HCl) (0.3 and 1 mg/kg, i.v.) and methamphetamine-HCl (MAP-HCl) (0.1 and 0.3 mg/kg, i.v.) increased the amplitude of the monosynaptic reflex (MSR). The increase of the MSR caused by PEA and MAP was antagonized by prazosin-HCl and abolished by the pretreatment with reserpine (i.p.) and 6-hydroxydopamine (intracisternally, 14 days previously). A dopamine D1 antagonist, SK&F 83566-HBr (0.01 mg/kg, i.v.), and a D2 antagonist. YM-09151-2 (0.3 mg/kg, i.v.), did not antagonize the increasing effects produced by PEA and MAP. An inhibitor of type-B monoamine oxidase, (-)deprenyl-HCl (1 mg/kg, i.v.), prolonged the effect of PEA but not that of MAP, suggesting that PEA alone, and not its metabolites, enhanced the MSR. These results suggest that PEA and MAP increase the amplitude of the MSR by releasing noradrenaline from the terminals of descending noradrenergic fibers, and that PEA, an endogenous trace amine, has a mechanism of action similar to that of MAP.     

Differential attenuation of somatovisceral and viscerosomatic reflexes by diazepam, phenobarbital and diphenylhydantoin.

In the chloralose-anaesthetized cat, stimulation of forelimb cutaneous afferent nerves evoked a response in the preganglionic splanchnic nerve, consisting of a short duration spinal reflex followed by a supraspinal component of longer duration. Diazepam (0·1–1·4 mg/kg, i.v.) markedly attenuated the supraspinal reflex but had a considerably lesser effect on the segmental response. On the other hand, diphenylhydantoin (10–40 mg/kg, i.v.) reduced predominantly the spinal component, whilst the supraspinal reflex was frequently enhanced after the initial dose of 10 mg/kg. This effect of diphenylhydantoin on the spinal reflex was direct, since it also occurred in the spinal cat. Phenobarbital (10–40 mg/kg, i.v.) was approximately equally potent in reducing both the spinal and supraspinal reflex. Visceromotor reflexes were markedly depressed by very small doses of diazephm (0·001 mg/kg, i.v.) and by larger doses of phenobarbital (10–20 mg/kg, i.v.). Diphenylhydantoin, although reducing this reflex, did not completely block it at the highest total dose tested (40 mg/kg, i.v.). The results indicate that the three CNS depressants differentially affect the spinal and supraspinal components of the somatosymphetic reflex. Furthermore, the three drugs also differ quantitatively from each other in depressing the spino-bulbo-spinal transmission of the viscerosomatic reflex.     

Reversal of the reserpine-induced ptosis by l-threo-3,4-dihydroxy-phenylserine (l-threo-DOPS), a (−)-norepinephrine precursor,and its potentiation by imipramine or nialamide

Summary The effect of l-threo-DOPS on the reserpine-induced ptosis in mice and its modification by imipramine, a norepinephrine (NE) uptake inhibitor, or nialamide, a monoamineoxidase inhibitor, were studied.Intraperitoneal (i.p.) injection of l-threo-DOPS (800 mg/kg) significantly reduced the severity of the ptosis. This reversal of the ptosis by l-threo-DOPS was markedly potentiated by i.p. injection of either imipramine (2.5 mg/kg) or nialamide (30 mg/kg). Response to l-threo-DOPS was also significantly potentiated by intracerebroventricular (i.c.v.) injection of imipramine (10 g). On the other hand, this treatment with imipramine (10 g, i.c.v.) also significantly potentiated the reversal of the ptosis by NE (20 g, i.c.v.), but the reversal by the subcutaneous (s.c.) injection of NE (1 and 3 mg/kg) was not affected.Reserpine (5 mg/kg, i.p.) markedly decreased the brain content of NE in mice, whereas l-threo-DOPS (400 mg/kg, i.p.) slightly restored it. Moreover, by the pretreatment with nialamide (30 mg/kg, i.p.), l-threo-DOPS produced a significant increase in the brain content of NE in reserpinetreated mice.These results suggested that l-threo-DOPS was capable of reversing the reserpine-induced ptosis due to the formation, at least in part of (–)-NE at the synaptic sites of central noradrenergic neurons.     

Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression

The effects of a selective 5-HT(6) receptor antagonist, SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide), were evaluated in behavioural tests sensitive to clinically effective anxiolytic- and antidepressant-compounds using diazepam and imipramine as reference drugs. In the Vogel conflict drinking test in rats, SB-399885 (1-3mg/kg i.p.) caused an anxiolytic-like activity comparable to that of diazepam (2.5-5mg/kg i.p.). An anxiolytic-like effect was also seen in the elevated plus-maze test in rats, where SB-399885 (0.3-3mg/kg i.p.) was slightly weaker than diazepam (2.5-5mg/kg i.p.). In the four-plate test in mice, SB-399885 (3-20mg/kg i.p.) showed an anxiolytic-like effect which was weaker than that produced by diazepam (2.5-5mg/kg i.p.). In the forced swim test in rats, SB-399885 (10mg/kg i.p.) significantly shortened the immobility time and the effect was stronger than that of imipramine (30mg/kg i.p.). In the forced swim test in mice, SB-399885 (20-30mg/kg i.p.) had an anti-immobility action, comparable to imipramine (30mg/kg i.p.) and also in the tail suspension test in mice, SB-399885 (10-30mg/kg i.p.) had an antidepressant-like effect, though was weaker than imipramine (10-20mg/kg i.p.). The tested 5-HT(6) antagonist (3-20mg/kg i.p.) shortened the walking time of rats in the open field test and, at a dose of 30mg/kg i.p. reduced the locomotor activity of mice. SB-399885 (in doses up to 30mg/kg i.p.) did not affect motor coordination in mice and rats tested in the rota-rod test. Such data indicate that the selective 5-HT(6) receptor antagonist SB-399885had specific effects, indicative of this compound's anxiolytic and antidepressant potential.     

Imipramine-induced antinociception in the formalin test. Receptor mechanisms involved and effect of swim stress

This study concerned the effect of swim stress on imipramine-induced antinociception in mice. The data showed that intraperitoneal (i.p.) administration of different doses of imipramine (10-40 mg/kg) and 0.5-3 min of swim stress (17 degrees C) induced antinociception in the first and second phases of the formalin test. Low period of swim stress (10 s) with low doses of imipramine (2.5, 5 and 10 mg/kg i.p.), which did not have any effect by themselves, in combination showed antinociception in the second phase of the test. Either yohimbine (0.5 mg/kg i.p.) or naloxone (1 mg/kg i.p.) reversed the response induced by the combination of low doses of imipramine plus swim stress. Yohimbine (1 mg/kg i.p.) decreased the response of imipramine (20 mg/kg i.p.) but not that of 30 s swim stress in the second phase. However, naloxone (1 mg/kg i.p.) reduced the antinociception induced by imipramine (20 mg/kg i.p.) or 30 s swim stress in the second phase of the test, the combination of imipramine with swim stress was not altered by yohimbine or naloxone. Prazosin induced antinociception by itself in the first phase of the test and increased swim-stress-induced antinociception with no interaction. It is concluded that antinociception induced by imipramine in the second phase of formalin test may be mediated through alpha(2)-adrenoceptor antagonists. The results indicate that the responses of swim stress and imipramine may be mediated by an opioid mechanism, but the combination of both drugs induced higher antinociceptive effects.     

Effects of a new dihydropyridine derivative, CV-4093.2HCl, on renal hemodynamics in spontaneously hypertensive rats

The effects of a new calcium antagonist, CV-4093.2HCl, on renal hemodynamics were examined in anesthetized and conscious spontaneously hypertensive rats (SHR). In the anesthetized rats, CV-4093.2HCl (5 and 10 micrograms/ kg, i.v.) showed a long-lasting hypotensive action, dilated renal vasculature, and increased renal blood flow. These renal hemodynamic actions of CV-4093.2HCl were more prominent than those of nicardipine (5 and 10 micrograms/kg). Moreover, CV-4093.2HCl (10 micrograms/kg, i.v.) inhibited renal vascular contractions induced by intravenous norepinephrine and angiotensin II. The inhibitory effect of CV-4093.2HCl was much more marked than that of nicardipine, although the inhibitory effects of both calcium antagonists on systemic pressor responses induced by the vasoactive substances were almost the same. In addition, CV-4093.2HCl (1 and 3 mg/kg, p.o.) increased blood flow in the kidneys but not in the other organs except for the small intestine in conscious SHR. These results suggest that CV-4093.2HCl has a relatively higher affinity for the renal vascular bed (renal resistance vessels), and its effect on renal hemodynamics seems to be beneficial for treating hypertension.