Effect of imipramine on the expression and acquisition of morphine-induced conditioned place preference in mice

The effect of imipramine and alpha-adrenoceptor agonists and antagonists on the acquisition or expression of morphine-induced conditioned place preference (CPP) was studied in mice. An unbiased CPP paradigm was used to study the effect of the agents. In the first set of experiments, the drugs were used during the development of CPP by morphine or they were used alone in order to see if they induce CPP or conditioned place aversion (CPA). Our data showed that intraperitoneal injection of morphine sulphate (2.5-10 mg/kg) induced CPP in mice. Imipramine (0.5-2.5 mg/kg), phenylephrine (0.5-2 mg/kg), yohimbine (0.5-2 mg/kg) or prazosin (0.1-1 mg/kg) did not influence CPP, but clonidine (0.002-0.05 mg/kg) induced CPA. Yohimbine increased, while clonidine and prazosin reversed, morphine-induced CPP. Phenylephrine did not influence the CPP induced by morphine. In the second set of experiments, when the drugs were used before testing on Day 6, in order to test their effects on the expression of morphine-induced CPP, imipramine (0.5-5 mg/kg) reversed morphine-induced CPP and this reversal was blocked by naloxone (2 mg/kg). Clonidine and prazosin reversed, while yohimbine decreased morphine-induced CPP. Phenylephrine did not alter the morphine response. Furthermore, yohimbine and prazosin reversed the imipramine effect. None of the drugs influenced locomotion. However, prazosin or yohimbine in combination with morphine altered locomotor activity during the acquisition of CPP. Yohimbine by itself increased locomotion. It is concluded that imipramine can induce CPA through an opioid receptor mechanism and alpha-adrenoceptor agents may influence morphine CPP.     

Alpha 2-adrenoceptor modulates the release of acetylcholine from the rostral ventrolateral medulla in response to morphine

The present study examined the role of the noradrenergic system in the modulation of acetylcholine (ACh) release in the rostral ventrolateral medulla (RVLM) using in vivo microdialysis of morphine. The basal level of ACh was 325.0 +/- 21.1 fmol/20 microl/15 min in the presence of neostigmine (10 microM). Intraperitoneal (i.p.) administration of 5 and 10 mg/kg morphine significantly increased ACh release by the RVLM. This enhancement was reversed by naloxone (1 mg/kg, i.p.). In addition, pretreatment with yohimbine (0.5 mg/kg, i.p.) or prazosin (0.2 mg/kg, i.p.) attenuated the systemic morphine-induced release of ACh in the RVLM. However, propranolol (0.2 mg/kg, i.p.) did not affect the morphine-induced ACh release. The addition of morphine (10(-4) M) to the perfusion medium increased the ACh release by 72.4% of the predrug values. The increased ACh release induced by local application of morphine was attenuated by pretreatment with yohimbine, but not prazosin. These findings suggest that morphine exerts an indirect stimulatory effect on the release of ACh by the RVLM and that the morphine-induced increase in ACh release is modulated by alpha2-adrenoceptors in freely moving rats.     

Clonidine produces mydriasis in conscious mice by activating central alpha 2-adrenoceptors

Intraperitoneal (i.p.) injection of the alpha 2-adrenoceptor agonist clonidine (1-3000 micrograms/kg) produced dose-dependent pupil dilatation in conscious C57/Bl/6 mice with an ED50 of 54 micrograms/kg (95% confidence limits 40-74 micrograms/kg). This response was rapid in onset and of approximately 30 min duration. The alpha 2-adrenoceptor antagonists idazoxan (1 or 3 mg/kg i.p.) and yohimbine (1 or 3 mg/kg i.p.) both produced dose-related miosis, but the alpha 1- and beta-adrenoceptor antagonists prazosin (1 or 3 mg/kg i.p.) and pindolol (1 or 3 mg/kg i.p.) were without effect. These doses of idazoxan and yohimbine potently reversed the mydriasis induced by clonidine (100 micrograms/kg i.p.), while prazosin and pindolol were again ineffective. Clonidine-induced mydriasis was also unaltered by the 5-HT antagonists, methysergide (2.5 mg/kg i.p.) and ketanserin (0.1 mg/kg i.p.) or 0.1 mg/kg i.p. of the dopamine antagonists, haloperidol, SCH 23390 and BRL 34778. A dose of 0.25 microgram clonidine, which was ineffective when administered i.p., produced marked mydriasis after intracerebroventricular (i.c.v.) injection. In addition, the mydriasis produced by i.p. injection of clonidine (100 micrograms/kg) was abolished by i.c.v. dosing of 2.5 micrograms idazoxan or yohimbine, but again not by prazosin or pindolol. Together, these data provide strong evidence to indicate that clonidine-induced mydriasis is exclusively mediated via central alpha 2-adrenoceptors and that this response provides a useful model for studying the function of these receptors.     

A centrally-mediated effect of morphine to diminish hepatocellular glutathione

Morphine administration has been associated with a decrease in hepatic glutathione (GSH) and an increase in the hepatotoxicity of compounds dependent upon GSH for detoxification. In this study, intraperitoneal administration of 100 mg/kg morphine in mice resulted in approximately a 25% decrease in hepatic GSH. The same magnitude of GSH depletion was also observed following intracerebroventricular (i.c.v.) injection of 100 μg of morphine, but no effect was observed when 100 μg of morphine was administered intravenously. Pretreating animals with either yohimbine (5 mg/kg, i.p.) or prazosin (5 mg/kg, i.p.) resulted in a partial blockade of i.c.v. morphine-induced change in hepatic glutathione concentrations. Adrenalectomy prior to i.c.v. morphine treatment completely prevented morphine-induced changes in hepatic GSH concentrations; however, the morphine response was restored in adrenalectomized mice supplemented with hydrocortisone (2.5 mg/kg). No effect on the ability of i.c.v. morphine to diminish GSH concentrations in the liver was observed following pretreatment with either propranolol (20 mg/kg, i.p.), atropine (1 mg/kg, i.p.), hexamethonium (15 mg/kg, s.c.), or destruction of peripheral adrenergic nerve terminals with 6-hydroxydopamine (30 mg/kg, i.p.). It is concluded that hepatocellular GSH concentrations may be diminished as a consequence of a central action of morphine. The response by liver GSH to this action does not appear to be mediated through adrenal medullary release of catecholamines or by autonomiC stimulation of the liver. While corticosteroids are a necessary component of this response, their role is probably permissive. The ability of both prazosin and yohimbine to antagonize the effect of i.c.v. morphine on hepatic GSH, coupled with the apparent absence of a peripheral catecholaminergic mechanism, suggests that the adrenergic interaction with the i.c.v. morphine effect is also of central origin. Thus, the results of this study show that the central effects of morphine can result in a decrease in hepatic GSH, and that this effect is not mediated by a peripheral catecholaminergic mechanism.     

Morphine state-dependent learning: interactions with alpha2-adrenoceptors and acute stress

The interactions of -adrenoceptors and acute restraint stress with morphine state-dependent memory of passive avoidance were examined in mice. Memory acquired following pre-training morphine administration (5 mg/kg, i.p.) was dose- and time-dependently retrieved by pre-test morphine; this effect was reversible by yohimbine (1 mg/kg). Pre-test clonidine (0.005-0.1 mg/kg) was also effective in restoring morphine-induced memory. Pre-training clonidine (2 mg/kg) induced an amnestic effect that was restorable by pre-test clonidine or morphine; this effect was also blocked by yohimbine. Acute pre-training stress for 2 h induced an amnestic effect that was reversible by pre-test morphine (1 and 5 mg/kg) or clonidine (0.01 and 0.1 mg/kg). Finally, acute pre-test stress could restore the impairment of memory induced by pre-training morphine. The data are suggestive of a functional interaction between -opioid, -adrenergic receptors and stress in modulating state-dependent learning and memory.     

The role of alpha-adrenoceptor mechanism(s) in morphine-induced conditioned place preference in female mice

It has been shown that the alpha-adrenergic system is involved in some effects of opioids, including analgesia and reward. Gender differences also exist between males and females in response to alpha-adrenergic agents. This study was designed to determine the effects of alpha-adrenoceptor agonists and antagonists on the acquisition or expression of morphine-induced conditioned place preference (CPP) in female mice. The experiments showed that subcutaneous injections of morphine (0.5-8 mg/kg) induced CPP in a dose-dependent manner in mice. Intrapritoneal administration of the alpha-1-adrenoceptor agonist, phenylephrine (0.03, 0.1 and 0.3 mg/kg), and alpha-2 adrenoceptor agonist, clonidine (0.0001, 0.0005 and 0.001 mg/kg), as well as alpha-1-adrenoceptor antagonist, prazosin (0.01, 0.05 and 0.1 mg/kg) or alpha-2 adrenoceptor antagonist, yohimbine (0.005, 0.01 and 0.05 mg/kg) did not induce motivational effects and also did not alter locomotor activity in the animals. In the second set of experiments, the drugs were used before testing on Day 5, to test their effects on the expression of morphine-induced CPP. Intrapritoneal administration of phenylephrine and clonidine decreased the expression of morphine-induced CPP. In contrast, after application of prazosin or yohimbine, the expression of morphine-induced CPP was increased. Administration of lower (0.03 mg/kg) and higher doses of phenylephrine (0.1 and 0.3 mg/kg) during acquisition of morphine CPP decreased and increased the morphine CPP, respectively. Similarly, the administration of prazosin and clonidine decreased while yohimbine increased the morphine CPP. It may be concluded that alpha-adrenoceptor mechanism(s) influence morphine-induced CPP in female mice.     

Effect of yohimbine on urethane-induced hyperglycemia in rats

Urethane is a widely used anesthetic and yohimbine is a well-known alpha 2-adrenergic antagonist. In fasted Wistar rats urethane at an anesthetic dose (1.25 g/kg, i.p.) caused an increase in plasma glucose, while pentobarbital at an anesthetic dose (40 mg/kg, i.p.) did not. Urethane caused no change in plasma glucose in adrenalectomized rats. The hyperglycemic effect of urethane was not inhibited by pretreatment with propranolol (1 mg/kg, p.o.) or prazosin (10 mg/kg, p.o.), but was reduced by pretreatment with phentolamine (10 mg/kg, p.o.) or yohimbine (10 mg/kg, p.o.). Urethane caused an elevation of plasma adrenaline, and yohimbine reduced the elevation. In addition, the pretreatment of yohimbine potentiated the urethane-induced increase in plasma insulin. These results indicate that yohimbine may inhibit the urethane-induced hyperglycemia that is mediated by the central and peripheral alpha 2-adrenergic systems.     

Blockade of alpha 2-adrenoceptors by 1-(2-pyrimidinyl)-piperazine (PmP) in vivo and its relation to the activity of buspirone

The effect of 1-(2-pyrimidinyl)-piperazine (PmP) and the parent drug, buspirone in counteracting the behavioral and biochemical effects of clonidine were evaluated in the rat. Intraperitoneal or oral administration of PmP, buspirone and yohimbine, but not of prazosin, antagonized the slowing of gastrointestinal motility induced by subcutaneous clonidine (0.1 mg/kg). The doses that inhibited the effect of clonidine on the transit time by 50% were 0.5 mg/kg i.p. and 0.7 mg/kg p.o. for PmP, 7 mg/kg i.p. and 9 mg/kg p.o. for buspirone and 0.5 mg/kg i.p. for yohimbine. PmP (0.5 mg/kg) did not block the antitransit effect of clonidine when administered by intracerebroventricular injection. The antitransit effect of a low dose of morphine (0.05 mg/kg i.p.) was not blocked by PmP (2 mg/kg i.p.). The prolongation of the hexobarbital-induced loss of the righting reflex that occurs after clonidine (0.25 mg/kg i.p.) administration was inhibited by pretreatment with PmP (0.1-2 mg/kg p.o.) or yohimbine (1 mg/kg i.p.) but not by pretreatment with prazosin (2 mg/kg i.p.). Buspirone (1-20 mg/kg) also reduced the effect of clonidine after oral administration, with a maximal effect at 5 mg/kg, whereas the same dose administered i.v. had less effect. PmP (2 mg/kg) and buspirone (15 mg/kg) raised the levels of total 3-methoxy-4-hydroxyphenylgycol (MHPG) in rat cerebral cortex, and prevented the decrease in MHPG induced by clonidine. These findings show that buspirone, in doses at which it is active as an anxiolytic, suppresses the central and peripheral effects of clonidine. This action occurs through alpha 2-adrenoceptors and is mediated primarily by the metabolite, PmP.     

Clonidine-induced hypoactivity and mydriasis in mice are respectively mediated via pre- and postsynaptic alpha 2-adrenoceptors in the brain

Since brain alpha 2-adrenoceptors occur both pre- and postsynaptically, experiments were carried out to determine the synaptic locations of those receptors mediating clonidine-induced hypoactivity and mydriasis. Intraperitoneal (i.p.) injection of clonidine (1-3000 micrograms/kg) to mice dose dependently induced these two responses and also decreased brain concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG). The ED50 values were: 120 micrograms/kg for hypoactivity (95% confidence limits 103-140 micrograms/kg), 54 micrograms/kg for mydriasis (95% confidence limits 40-74 micrograms/kg) and 18 micrograms/kg for MHPG reduction (95% confidence limits 8-36 micrograms/kg) suggesting that these responses could all be presynaptically mediated. However, methamphetamine which increases noradrenaline turnover was found to dose dependently produce mydriasis, but not hypoactivity, after peripheral (0.1-5 mg/kg i.p.) or central (0.5-10 micrograms i.c.v.) injection. The mydriasis produced by methamphetamine (0.5 mg/kg i.p.) was abolished by i.c.v. injection of 1 micrograms idazoxan or yohimbine, but not 2.5 micrograms prazosin or pindolol, showing this effect was mediated by central alpha 2-adrenoceptors. Methamphetamine (1-10 micrograms i.c.v.) potentiated the mydriasis induced by clonidine (50 micrograms/kg i.p.) suggesting this was a postsynaptic alpha 2-adrenoceptor response. By contrast, methamphetamine (1-10 micrograms i.c.v.) dose dependently reversed clonidine (100 micrograms/kg i.p.) hypoactivity indicating this response was mediated by presynaptic alpha 2-adrenoceptors. These hypotheses were confirmed by destruction of noradrenergic neurones using DSP-4 (100 mg/kg i.p. x 2). This treatment prevented the mydriasis response to methamphetamine (0.5 mg/kg i.p.), but not clonidine (100 micrograms/kg i.p.) and markedly attenuated clonidine (100 micrograms/kg i.p.) hypoactivity.     

Clonidine and guanfacine-induced antinociception in visceral pain: possible role of alpha 2/I2 binding sites

Visceral pain is one of the most common forms of pain which is poorly understood. We now studied the influence of imidazoline/guanidinium compounds such as clonidine and guanfacine on visceral pain in the presence or absence of yohimbine and benazoline. To produce visceral pain-related behaviours, formalin (10%) was administered by inserting a fine cannula into the colon via the anus. Each experiment took 1 h. Clonidine (0.001, 0.01 and 0.1 mg/kg, i.p.) and guanfacine (2.5, 5 and 10 mg/kg, i.p.) produced analgesia dose dependently. The clonidine response was inhibited by yohimbine (0.2 mg/kg, i.p.). On the other hand, benazoline (5 mg/kg, i.p.) blocked the antinociceptive effect of guanfacine (5 mg/kg). Benazoline (2.5 and 5 mg/kg) itself also induced analgesia in inflammatory colonic pain. In this study, we used morphine to ensure that the behavioural responses were pain-related. Our results showed that morphine (2.5, 5 and 10 mg/kg, s.c.) produced a dose-dependent antinociception. The morphine (7 mg/kg, s.c.) response was reduced by naloxone (2 mg/kg, i.p.). However, we concluded that both imidazoline (I(2)) and alpha(2)-adrenoceptors may play a role in producing analgesia in visceral pain.     

Alpha-2 agonists decrease expression of morphine-induced conditioned place preference

Opioidergic system can interact with different transmission such as dopaminergic and adrenergic system. It has been shown that alpha-adrenergic system is involved in some effects of opioid including reward. In this study, alpha-2 agonists were used before testing on day 6 to evaluate their effects on the expression of morphine-induced conditioned place preference (CPP). Our results showed that intraperitoneal (i.p.) injections of morphine (5 mg/kg) induced CPP. Administration of alpha(2)-agonists clonidine (0.01, 0.02 and 0.04 mg/kg, i.p.), tizanidine (0.1, 0.2 and 0.4 mg/kg, i.p.) and xylazine (2.5, 5 and 10 mg/kg, i.p.) decreases the expression of morphine-induced CPP. Yohimbine (0.5 mg/kg, i.p.) reversed the inhibitory effect of alpha(2)-agonists. The comparison of potency of inhibitory effect of three agonists showed that ID(50) values for clonidine, tizanidine and xylazine were 0.013, 0.32 and 1.86 mg/kg respectively. Therefore, it is concluded that alpha(2)-agonists decrease the morphine-induced CPP in mice and clonidine is more potent than tizanidine and xylazine. The relative potency of clonidine with respect to tizanidine and xylazine was 30 and 180 respectively.     

Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for ��-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate.     

Antagonism of apomorphine-enhanced startle by alpha 1-adrenergic antagonists

The present study investigated the possible involvement of central noradrenergic neurons in mediating the excitatory effect of the dopamine agonist apomorphine on the acoustic startle response in rats. Experiment 1 assessed the effects of intraperitoneal (i.p.) administration of adrenergic antagonists on apomorphine-enhanced startle. The excitation of startle produced by apomorphine (1.0-3.0 mg/kg i.p.) was blocked by the alpha 1-adrenergic antagonists prazosin (0.03-1.0 mg/kg) and WB-4101 (1.0 mg/kg). Prazosin was very potent in this regard, having an ED50 of 0.03 mg/kg. Blockade of beta-adrenergic receptors with propranolol (20 mg/kg) or blockade of peripheral alpha-adrenergic receptors with phentolamine (10 mg/kg) failed to alter the effect of apomorphine. Prazosin did not block the enhancement of startle produced by other drugs (5-methoxy-N,N-dimethyltryptamine, strychnine), nor did it alter the entry of apomorphine into the brain. The alpha 1-adrenergic antagonists piperoxane (0.03 mg/kg), yohimbine (0.03 mg/kg) or RX781094 (0.07 mg/kg) markedly potentiated apomorphine excitation. These data indicated that specific blockade of central alpha 1-adrenergic receptors prevents apomorphine-enhanced startle. In contrast to the effects of alpha 1-adrenergic antagonists, Experiment 2 found that other drugs that produce an acute (clonidine, 0.040 mg/kg) or chronic (intraventricular 6-hydroxydopamine, 2 X 200 micrograms; DSP4, 50 mg/kg i.p.) disruption of noradrenergic transmission failed to affect apomorphine excitation. Thus, the ability of alpha 1-adrenergic antagonists to block apomorphine's excitation of startle cannot be explained by a simple dopamine-norepinephrine interaction. Alternative hypothesis are discussed.     

The effects of simultaneous administration of alpha(2) -adrenergic agents with L-NAME or L-arginine on the development and expression of morphine dependence in mice

Both alpha(2)-adrenoceptors and the L-arginine/nitric oxide (NO) pathway have been implicated in the modulation of morphine dependence. This study examined the effects of simultaneous administration of the alpha(2)-adrenoceptor agonist clonidine or the antagonist yohimbine together with the NO precursor L-arginine or the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on the induction and expression of morphine dependence as assessed by naloxone-precipitated withdrawal jumping and diarrhoea. Male NMRI mice weighing 20-30 g were used. In the induction phase, clonidine (0.01-0.1 mg/kg) intensified and yohimbine (0.5-2 mg/kg) attenuated the degree of morphine dependence. Yohimbine reversed the effect of clonidine. L-NAME (5 and 10 mg/kg) did not affect the development of morphine dependence, but significantly potentiated the effects of both subeffective (0.01 mg/kg) and effective (0.03 mg/kg) doses of clonidine. L-Arginine did not alter morphine dependence but inhibited the effect of clonidine. The effects of yohimbine in the induction phase were attenuated by L-NAME, but were not significantly affected by L-arginine. In the expression phase, clonidine attenuated and yohimbine intensified the signs of dependence. The effect of clonidine was inhibited by yohimbine. In the expression phase, L-NAME attenuated the withdrawal syndrome at 10 mg/kg and showed potentiation with clonidine in suppressing withdrawal signs. L-Arginine did not alter morphine dependence, but at 20 mg/kg inhibited and at 100 mg/kg potentiated the attenuating effect of clonidine on the expression of withdrawal syndrome. The effect of yohimbine on the expression phase was also attenuated by L-NAME, but was not significantly affected by L-arginine. In conclusion, alpha(2)-adrenergic and NO pathways seem to be functionally linked in the modulation of opioid dependence.     

Precipitation by yohimbine of the withdrawal syndromes of clonidine, guanfacine, and methyldopa in the spontaneously hypertensive rat

In conscious spontaneously hypertensive (SH) rats, continuously infused with clonidine (500 micrograms/kg/day s.c.) for 12 days, yohimbine (3 or 10 mg/kg i.p.) dose dependently precipitated an overshoot of heart rate and other withdrawal symptoms, such as blood pressure upswings, diarrhea, ptosis, body shivering, jumping, and wet-dog shakes. Naloxone (3 or 30 mg/kg i.p.) or prazosin (1 mg/kg i.p.) did not evoke withdrawal signs in clonidine-treated SH rats. In SH rats treated for 12 days with guanfacine (10 mg/kg/day s.c.), the administration of yohimbine elicited a withdrawal pattern similar in severity and appearance to that observed in clonidine-treated rats. In methyldopa-treated (200 mg/kg/day) SH rats, the yohimbine-precipitated withdrawal symptoms were much less pronounced than those observed in the clonidine- and guanfacine-treated animals, despite the equipotency of the infusions in reducing mean arterial pressure. These results indicate that the clonidine-withdrawal syndrome can be precipitated by acute alpha 2-adrenoceptor blockade. The previously observed minor severity of the guanfacine-discontinuation syndrome in the rat should be attributed to the longer half-life of this drug as compared to clonidine. On the other hand, alpha-methylnoradrenaline much less intensively triggers the mechanisms underlying withdrawal symptoms than clonidine or guanfacine.     

Pharmacological studies of celiprolol: II. Alpha 2-Adrenoceptor blocking effects of a cardioselective beta-blocker, celiprolol

alpha-Adrenoceptor blocking effects of the cardioselective beta-blocker celiprolol were tested. 1. Celiprolol antagonized the contractions induced by UK-14304, but not those by phenylephrine, in isolated rat tail arteries with a pA2 value of 4.95. 2. In the isolated rat vas deferens, twitch contractions elicited by the transmural electrical stimulation (TS) were almost blocked by TTX (10(-7) M). Clonidine inhibited the TTX-sensitive contraction in a concentration-dependent manner. Celiprolol produced little effect on the inhibitory effects of clonidine. The concentration-inhibition curve of clonidine was shifted to the right by yohimbine (10(-8) M), but not by prazosin (10(-8) M). 3. Although celiprolol slightly increased the 3H-efflux to TS from the [3H]-norepinephrine-loaded rat vas deferens, the increment was not significant. Yohimbine (10(-7) M) significantly increased the 3H-efflux. TTX (10(-7) M) and bretylium (3 x 10(-5) M) blocked the 3H-efflux. 4. In the spinal rat treated with propranolol (3 mg/kg, i.v.) and prazosin (0.1 mg/kg, i.v.), celiprolol (30 and 100 mg/kg, i.v.) and yohimbine (0.1-1 mg/kg, i.v.) inhibited the pressor response to clonidine. 5. These results indicate that celiprolol may have a weak alpha 2-blocking effect which was more effective on postsynaptic alpha 2-receptors than presynaptic ones.     

5-HT3 receptor antagonists inhibit the response of kappa opioid receptors in the morphine-induced Straub tail [corrected

We used the morphine-induced Straub tail to examine the actions of a 5-HT₃ receptor antagonist and κ opioid receptor agonist. The κ opioid receptor agonist, U-50,488H (4–16 mg/kg i.p.), produced a dose-related inhibition of the tail elevation induced by morphine (10 mg/kg s.c.) in ICR male mice. ICS-205-930 (3 and 10 mg/kg i.p.) and zacopride (0.3 and 1 mg/kg i.p.), 5-HT₃ receptor antagonists, attenuated the inhibitory effect of U-50,488H in a dose-dependent manner. ICS-205-930 and zacopride did not inhibit the morphine-induced Straub tail. These observations suggest that the actions of κ opioid receptors may be modulated by 5-HT³ receptors in the morphine-induced Straub tail.     

Mechanism of action of apomorphine on rat gastric secretion

The effects of apomorphine on the volume of gastric secretion and its content of H+, K+, Na+ and Cl- were determined in conscious rats having gastric cannulas. Apomorphine dose-dependently (0.25-0.5 mg/kg s.c.) decreased the volume of gastric secretion, its acid concentration and, at the highest dose, Cl- concentration. However, Na+ and K+ concentrations were unchanged. The alpha 1- and alpha 2-adrenoceptor antagonists prazosin (0.25-0.5 mg/kg i.p.) and yohimbine (5-10 mg/kg i.p.), the beta 1- and beta 2-adrenoceptor antagonist propranolol (5 mg/kg i.p.), the beta 2-adrenoceptor antagonist ICI 118551 (1 mg/kg i.p.) and the dopamine receptor antagonists haloperidol (0.25-2.5 mg/kg i.p.), metoclopramide (2.5-10 mg/kg i.p.) or domperidone (2.5 mg/kg i.p.), administered alone, had little or no effect on the volume, H+, Na+ or Cl- concentrations of gastric secretion. Propranolol prevented the action of apomorphine to reduce the volume of gastric secretion but failed to modify the reductions in H+ and Cl- concentrations. The action of propranolol was mimicked by ICI 118551 but not by the beta 1-adrenoceptor antagonist atenolol. Yohimbine, prazosin or domperidone had little or no effect on the actions of apomorphine. Haloperidol (0.5 mg/kg i.p.) and metoclopramide (10 mg/kg i.p.) antagonised apomorphine's action to reduce H+ and Cl- concentrations but significantly enhanced the action of apomorphine to reduce the volume of gastric secretion. The results suggest that the ability of apomorphine to reduce the volume of gastric secretion is mediated via beta 2-adrenoceptors whilst acid concentration is reduced via an action on neuroleptic sensitive receptors.     

Effects of yohimbine on morphine analgesia and physical dependence in the rat.

The effects of yohimbine on morphine analgesia and on the development of opiate physical dependence were studied to find out more about the involvement of alpha 2-adrenergic mechanisms in opioid actions. Male Sprague-Dawley rats (250-300 g) were used. The acute effect of morphine (5 mg/kg i.p.) in the tail-flick test was reduced significantly by pretreatment with a single dose of yohimbine (2 mg/kg i.p.). Alone yohimbine, produced a slight hyperalgesia. Animals treated with a sustained-release preparation of morphine (300 mg/kg s.c.) showed the same sensitivity to opiate analgesia 72 h later whether they were treated concomitantly with yohimbine or not, but they exhibited fewer withdrawal symptoms upon naloxone injection after yohimbine (2 or 4 mg/kg i.p. 24, 28, 48 and 52 h after the start of systemic morphine treatment). The results obtained confirm previous data on the effects of yohimbine on morphine analgesia and reveal the importance of alpha 2-adrenergic activation in the development of opioid physical dependence.     

5-HT3 receptor antagonists inhibit the response of κ oploid receptors in the morphine-reduced straub tail

We used the morphine-induced Straub tail to examine the actions of a 5-HT₃ receptor antagonist and κ opioid receptor agonist. The κ opioid receptor agonist, U-50,488H (4–16 mg/kg i.p.), produced a dose-related inhibition of the tail elevation induced by morphine (10 mg/kg s.c.) in ICR male mice. ICS-205-930 (3 and 10 mg/kg i.p.) and zacopride (0.3 and 1 mg/kg i.p.), 5-HT₃ receptor antagonists, attenuated the inhibitory effect of U-50,488H in a dose-dependent manner. ICS-205-930 and zacopride did not inhibit the morphine-induced Straub tail. These observations suggest that the actions of κ opioid receptors may be modulated by 5-HT³ receptors in the morphine-induced Straub tail.