Behavioral sensitization to cocaine: cooperation between glucocorticoids and epinephrine

Rationale  Stressful life experiences facilitate responsiveness to psychostimulant drugs. While there is ample evidence that adrenal glucocorticoids mediate these effects of stress, the role of the sympatho-adrenal system in the effects of psychostimulants is poorly understood. Objectives  The present study investigated the role of the two adrenal stress hormones, corticosterone and epinephrine, in sensitization to the locomotor stimulant effects of cocaine. Materials and methods  The DBA/2 mouse strain was used, as behavioral sensitization in this strain critically depends on adrenal hormones. Animals were subjected to adrenalectomy (“ADX”, surgical removal of the adrenals) or SHAM surgery, and ADX mice were given replacement of epinephrine (5 × 10⁻³ mg/kg subcutaneously (s.c.) just prior to each drug administration), corticosterone (20%, s.c., pellet), or both. Mice were subjected to a cocaine sensitization regimen (15.0 mg/kg cocaine on nine consecutive days followed by a 7.5 mg/kg cocaine challenge after a 5-day withdrawal). Results  In agreement with our previous observations, ADX prevented initiation and expression of cocaine-induced locomotor sensitization. Whereas neither corticosterone nor epinephrine alone were sufficient to reverse the ADX effect, both hormones were necessary to fully restore initiation and retention of sensitization to levels observed in SHAM animals. Conclusions  The present findings indicate that corticosterone and epinephrine cooperate to facilitate behavioral responsiveness to cocaine. These data emphasize that in addition to the hypothalamic–pituitary–adrenal axis, the sympathetic nervous system plays a critical role in psychostimulant sensitivity.     

International symposium on the brain-gut axis: A new frontier: Florence (Italy), June 29–Juli 1, 1981

Hemorrhage, 15 ml/kg induced a rapid fall of blood pressure in intact and anephric cats, but only intact cats demonstrated significant blood pressure recovery following bleeding. Naloxone, 0.1 mg/kg · min, i.v., had a mild promoting effect on blood pressure recovery in the intact cats whereas, in the hemorrhaged anephric cats naloxone re-established an almost complete recovery of blood pressure. These results suggest that endogenous opioid substances play a significant depressor role in hemorrhagic shock, especially in anephric animals.     

Choline potentiates the pressor response evoked by glycyl-glutamine or naloxone in haemorrhaged rats

1. Severe blood loss initially lowers arterial pressure through a central mechanism that is thought to involve opioid and cholinergic neurons. The present study tested the hypothesis that simultaneous administration of a cholinergic agonist and an opioid receptor antagonist would produce a synergistic effect in the treatment of haemorrhage. Specifically, we tested whether choline, a precursor of acetylcholine, potentiates the pressor effect of the beta-endorphin derived peptide glycyl-glutamine (Gly-Gln) or the opioid receptor antagonist naloxone following acute haemorrhage. 2. Conscious rats were treated intracerebroventricularly (i.c.v.) with choline chloride (180 nmol) alone or combined with Gly-Gln (10 nmol) or naloxone (10 nmol) 2 min after blood withdrawal (2.5 mL/100 g bodyweight over 20 min) was completed; mean arterial pressure and heart rate were monitored for 30 min. 3. Combined treatment with choline and Gly-Gln elevated mean arterial pressure but did not affect heart rate significantly. Choline and Gly-Gln had no effect on cardiovascular function when administered alone to haemorrhaged rats or when given together to normotensive animals. Choline also potentiated the pressor and tachycardic effect of naloxone in haemorrhaged rats. 4. These data show that choline potentiates the pressor effect of Gly-Gln and naloxone in haemorrhaged rats.     

Paradoxical effect of naloxone on the hemorrhagic hypotension in normotensive and spontaneously hypertensive Wistar-Kyoto rats.

The influence of naloxone on recovery from hemorrhagic hypotension was investigated in conscious normotensive and spontaneously hypertensive (SHR) Wistar-Kyoto rats. In both groups arterial blood pressure (MBP) was reduced to 50% of the resting level by arterial bleeding. Administration of naloxone (0.02 mg/kg iv) significantly impaired restitution of MBP in WKY and SHR in comparison to control experiments on WKY and SHR receiving no naloxone. The magnitude of this effect was similar in both strains, however in SHR, it appeared with a significant delay. The results indicate that small doses of naloxone may suppress recovery from hemorrhagic hypovolemia.     

Developmental responses to opioids reveals a lack of effect on stress-induced corticosterone levels in neonatal rats.

The neonate has an unusual capacity for survival and the possibility exists that mechanisms for controlling stress responses may differ in the developing animal. In adults both endogenous and exogenous opioids can modulate the corticosterone responses to stress. We have studied this effect in neonatal rats and found that opioid modulation is absent in early postnatal development. Neonatal rats of either sex were injected with morphine (5-50 mg kg-1), fentanyl (10-100 micrograms kg-1), buprenorphine (0.1-30 mg kg-1) or naloxone (0.1-10 mg kg-1) and plasma corticosterone measured fluorimetrically 15 or 20 min later. In addition naloxone reversibility studies (1 mg kg-1, co-administered) were carried out for the opioid agonists. In adult rats, elevations in plasma corticosterone caused by injection stress were potentiated by morphine, fentanyl and buprenorphine. In neonates, though injection stress-induced rises in plasma corticosterone were absent at 10 days, elevations were observed at 21 days and later. However, significant potentiation of this corticosterone response by fentanyl was absent at 21 days and at later ages (30 and 40 days) for morphine and buprenorphine. The potentiating effect of all three agonists did not become fully effective until day 45. In addition, in animals acclimatized to injection stress by 7 day injection pretreatment, fentanyl did not significantly alter corticosterone levels in 30 day old neonates. High doses of naloxone (10 mg kg-1) significantly increased the corticosterone response to injection stress in adult rats but this effect was absent in 30 day old animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the cardiovascular effects of meptazinol and naloxone following haemorrhagic shock in rats and cats.

The cardiovascular effects of the opioid mixed agonist-antagonist, meptazinol, and the opioid antagonist, naloxone, have been evaluated in conscious rats, anaesthetized rats and anaesthetized cats following the induction of haemorrhagic shock. The mean arterial pressure of conscious rats decreased by 17-29 mmHg following a haemorrhage of 20% of blood volume. Meptazinol (17 mg kg-1, i.m.) administered after haemorrhage evoked a rapid and sustained increase in mean arterial pressure to pre-haemorrhage levels. Naloxone (10 mg kg-1, i.v.) also increased mean arterial pressure to a level significantly higher than post-haemorrhage values. Neither haemorrhage nor subsequent drug treatments evoked significant changes in the heart rates of conscious rats. In anaesthetized rats, 20% haemorrhage evoked decreases in mean arterial pressure, heart rate and cardiac output. Blood flow to the heart, skin, skeletal muscle, kidneys, spleen and liver (arterial) was decreased. Meptazinol and naloxone increased blood pressure and total peripheral resistance, but did not significantly alter heart rate or cardiac output. Hepatic arterial flow decreased further in both drug and vehicle treated groups. In addition meptazinol slightly reduced skeletal muscle flow. In anaesthetized cats 40% haemorrhage decreased mean arterial pressure by 46 +/- 3 mmHg. An intravenous infusion of either meptazinol or naloxone (cumulative 2 mg kg-1, i.v.) partially restored blood pressure. In experimental animal models of haemorrhagic shock, meptazinol has a similar cardiovascular profile to naloxone. The established analgesic activity of meptazinol may confer an advantage in some shock states.     

Interaction of corticosterone and nicotine in regulation of prepulse inhibition in mice

The aim of the present study was to investigate if different levels of circulating corticosterone (CORT) modulate the effect of nicotine on prepulse inhibition (PPI), a measure of sensorimotor gating that is disrupted in schizophrenia and other mental illnesses. Four groups of mice were investigated: sham-operated, adrenalectomized (ADX) and implanted with a cholesterol pellet, ADX and implanted with a 10 mg CORT pellet, or ADX and 50 mg of CORT. Different CORT levels or doses of nicotine did not significantly affect startle responses. Baseline PPI was significantly reduced in mice implanted with the highest dose of CORT. In ADX mice implanted with cholesterol, nicotine treatment influenced PPI depending on the prepulse intensity. In ADX mice implanted with 50 mg of CORT, treatment with 10 mg/kg of nicotine caused a significant increase in PPI at all prepulse intensities. Binding studies showed that corticosterone treatment had significantly affected nicotinic acetylcholine receptor (nAChR) density in the mouse brain. Treatment with 50 mg CORT decreased 125I-epibatidine binding in the globus pallidus and 125I-alpha-bungarotoxin binding in the claustrum. These results suggest a possible interaction of corticosterone and nicotine at the level of the alpha4- and alpha7-type nAChR in the regulation of PPI. In situations of high circulating levels of corticosterone, nicotine may be beneficial to restore disruption of PPI.     

FACTORS INFLUENCING THE EFFECTS OF INTRAVENOUS NALOXONE ON ARTERIAL PRESSURE AND HEART RATE AFTER HAEMORRHAGE IN CONSCIOUS RABBITS

The circulatory responses to different intravenous doses of naloxone were studied in conscious rabbits before and after haemorrhage, under different conditions including prior ganglion blockade. Unless there had been blood loss, naloxone elicited no pressor response, even in high dose. After bleeding so that arterial pressure fell to 40 mmHg, the dose-response relationship for naloxone had two components. Over a low-dose range (threshold 0.3 mg/kg) naloxone had a modest pressor effect but did not affect heart rate. Over a much higher dose range (threshold 0.6 mg/kg) naloxone caused a marked rise in arterial pressure and a profound bradycardia. The highest dose of naloxone examined (25 mg/kg) caused a rise in arterial pressure of 70 mmHg and a reduction in heart rate of 160 beats/min. The pressor and bradycardic effects of naloxone were the same whether post-haemorrhagic hypotension lasted 5, 10, 20 or 30 min. The responses to naloxone in low or high dose depended much more closely on the volume of blood removed than on the level to which arterial pressure fell. Even after non-hypotensive haemorrhage a high dose of naloxone had marked pressor and bradycardic effects. Ganglion blockade prior to haemorrhage abolished the pressor response to a low, but not to a high, dose of naloxone. It was concluded that prolonged and severe hypotension are not necessary to 'prime' the cardiovascular system to respond to naloxone after haemorrhage. In a high dose its pressor effects appear to be mediated post-ganglionically, but in a low dose it may act within the central nervous system.     

Serotonin modulates the suppressive effects of corticosterone on proliferating progenitor cells in the dentate gyrus of the hippocampus in the adult rat.

This series of experiments explores the interaction between corticosterone and serotonin (5-HT) in the regulation of cell proliferation in the dentate gyrus of the adult rat. Intracerebroventricular 5,7-DHT (5,7-dihydroxytryptamine) (either 200 or 300 microg) resulted in highly significant depletion of 5-HT as measured by high performance liquid chromatography in the frontal cortex but had no effect on the number of proliferating cells in the dentate gyrus by measuring 5-bromo-2'-deoxyuridine (BrdU) and Ki-67 cytochemistry. Treatment with PCPA (p-chlorophenylalanine: a tryptophan hydroxylase inhibitor: 300 mg/kg initially followed by 100 mg/kg/day) resulted in reduced proliferation as measured by Ki-67 after 3 days treatment, but not by BrdU uptake, and not after 14 days treatment by either method. In addition, injection of corticosterone (10-40 mg/kg/day) for 8 days significantly reduced proliferation in the dentate gyrus, as expected, measured by both BrdU uptake and Ki-67 immunostaining. Adrenalectomized (ADX) rats with a replacement subcutaneous pellet of corticosterone showed reduced proliferation when given additional corticosterone (10 mg/kg/day for 8 days), but this was prevented by 5-HT depletion (i.c.v. 5,7-DHT). Finally, a dose-response study showed that progressive doses of corticosterone (0-40 mg/kg/day) in ADX rats resulted in diminished suppression of proliferation in 5-HT-depleted compared with 5-HT-intact rats. These results strongly suggest that 5-HT regulates the sensitivity of proliferating cells in the dentate gyrus to corticosterone.     

Cannabinoid CB(1) receptor blockade enhances the protective effect of melanocortins in hemorrhagic shock in the rat

Activation of peripheral cannabinoid CB(1) receptors contributes to hemorrhagic hypotension, and endocannabinoids produced by macrophages and platelets may be mediators of this effect. A number of studies have provided evidence that functional links exist in the mechanisms of action of cannabinoids and opioid peptides; and opioids too play an important role in the pathophysiology of hemorrhagic hypotension and shock. On the other hand, melanocortin peptides, which are the main endogenous functional antagonists of opioid peptides, have an antishock effect in animals and humans. Thus, we investigated whether an interaction exists between endocannabinoids and the endogenous opioid/antiopioid system also in a condition of hemorrhagic shock and, particularly, whether the blockade of cannabinoid CB(1) receptors potentiates the antishock effect of melanocortins. Urethane-anesthetized rats were stepwise bled until mean arterial pressure decreased to, and stabilized at, 21-23 mm Hg. In this model of hemorrhagic shock, which caused the death of all control rats within 30 min after vehicle (tween 80, 5% in saline) injection, the intravenous (i.v.) bolus injection of the cannabinoid CB(1) receptor antagonist N-piperidino-5-[4-chlorophenyl]-1-[2,4 dichlorophenyl]-4-methyl-3-pyrazolecarboxamide (SR141716A) increased mean arterial pressure, pulse pressure, respiratory rate and survival rate in a dose-related manner (0.1-3 mg/kg), an almost complete recovery of mean arterial pressure, pulse pressure and respiratory rate, and 100% survival at the end of the observation period (2 h), occurring with the dose of 3 mg/kg. The melanocortin ACTH-(1-24) (adrenocorticotropin) also produced in a dose-related manner (0.02-0.16 mg/kg i.v.) a restoration of cardiovascular and respiratory functions, and increased survival rate, an almost complete recovery and 100% survival at the end of the observation period (2 h) occurring with the dose of 0.16 mg/kg. When a subactive dose of SR141716A (0.2 mg/kg; 30% survival) was associated with a subactive dose of ACTH-(1-24) (0.02 mg/kg; 12% survival), a complete reversal of the shock condition was obtained with 100% survival at the end of the 2-h observation period. The present results show that the concurrent inhibition of both endogenous opioid and cannabinoid systems produces a reversal of hemorrhagic shock more effective than that produced by the inhibition of either of them. These data suggest that functional interactions between endocannabinoids and opioid/antiopioid are at work also in the pathophysiology of hemorrhagic shock.     

Role of endogenous opioids on ventilation and chemical control of breathing in pentobarbitone-anesthetized rats

To investigate the role of endogenous opioids on ventilatory control in pentobarbitone-anesthetized rats, the opioid antagonists naloxone and naltrexone were studied for their effects on ventilation, arterial blood gases and on ventilatory responses to hypoxia and carbon dioxide. In animals breathing room air, intravenous administration of naloxone and naltrexone (4 and 10 mg/kg) caused a dose-related increase in tidal volume, respiratory rate and minute volume. These ventilatory responses were rapid in onset and were associated with a decrease in arterial PaCO2, an increase in arterial pH and an increase in arterial PaO2. Intravenous naloxone (4 mg/kg) antagonized the increase in PaCO2 and decrease in arterial pH induced by the administration of morphine (3 mg/kg, i.v.). In animals breathing 100% O2, intravenous administration of naloxone and naltrexone (4 and 10 mg/kg) did not stimulate ventilation. Furthermore, intracerebroventricular administration of naloxone (15 and 150 micrograms) had no measurable effect on ventilation. Ventilatory responses to both hypoxia and carbon dioxide were not augmented by intravenous naloxone (4 mg/kg) and naltrexone (4 and 10 mg/kg). In fact, the increase in respiratory rate due to hypoxia was significantly (p less than 0.05) reduced by naltrexone (10 mg/kg, i.v.). In conclusion, our results demonstrate that naloxone and naltrexone caused hyperventilation in pentobarbitone-anesthetized rats. This effect was probably triggered by stimulation of the peripheral arterial chemoreceptors and did not involve mechanisms directly associated with the central nervous system. However, endogenous opioids were not involved in the chemical control of breathing in pentobarbitone-anesthetized rats since ventilatory responses to hypoxia and carbon dioxide were not changed by administration of these opioid antagonists.     

Facilitation of ethanol consumption by intracerebroventricular infusions of corticosterone

Male Wistar rats bearing intracerebroventricular (ICV) cannulae and with simultaneous access to 6% ethanol and water were subjected to adrenalectomy (ADX) or sham surgery. ADX decreased ethanol intake. Starting a few days later, the animals received ICV infusions with 100 μg corticosterone acetate (CORT) with 2-to 3-day intervals for 2 weeks. ICV CORT, but not SC CORT at the same dose, restored ethanol consumption in ADX rats to preoperative levels, whereas vehicle infusions (propylene, glycol) did not. Adrenally intact animals, which normally consumed moderate amounts of ethanol (≈0.5 g/kg per day), also showed a robust effect of ICV infusions of CORT, whereas this facilitatory effect was not observed in high consumers (≈3.0 g/kg per day). The suppressive effect of ADX on ethanol intake was not reproduced by concurrent and repeated ICV infusions of intracellular mineralocorticoid (RU 28318) and glucocorticoid (mifepristone) receptor blockers. It is concluded that CORT stimulates alcohol consumption by acting in the brain, probably by way of neuronal membrane mechanisms.     

Endogenously released opioids mediate meal-induced gastric relaxation via peripheral mu-opioid receptors

Aliment Pharmacol Ther 2011; 33: 607–614

Summary

Background The centrally acting mu‐opioid receptor antagonist naloxone inhibits meal‐induced gastric accommodation. Aim To study the role of peripheral mu‐opioid receptors in the regulation of gastric tone and food intake by comparing the effects of naloxone with the peripherally restricted mu‐opioid receptor antagonist methylnaltrexone. Methods Methylnaltrexone (12 mg s.c.), naloxone (20 μg/kg/h intravenous infusion after 0.4 mg bolus) and placebo were studied in 23 healthy volunteers. Gastric volume was recorded using an intragastric bag held at constant pressure connected to a barostat, with administration of a nutrient drink after 30 min. Pressure in the stomach was measured during intragastric nutrient drink infusion until the volunteers scored maximal satiation. Results Methylnaltrexone inhibited significantly the volume increase after food intake as assessed with the barostat (P < 0.01). During nutrient drink infusion the intragastric pressure significantly decreased as compared with the preprandial pressure after placebo treatment. Both methylnaltrexone and naloxone significantly inhibited this intragastric pressure decrease (P < 0.001 and P < 0.05, respectively). Volunteers scored maximal satiation after 979 ± 96, 958 ± 84 and 1124 ± 107 mL nutrient drink infused (for naloxone, methylnaltrexone and placebo treatment, respectively; P < 0.05). Conclusions These results indicate that endogenous opioids mediate gastric accommodation and satiation via peripheral mu‐opioid receptors. Effects were less pronounced after naloxone treatment, which indicates that centrally involved mu‐opioid receptors mediate an opposing effect.     

Modulation of emesis by fentanyl and opioid receptor antagonists in Suncus murinus (house musk shrew).

The anti-emetic mechanism of action of fentanyl to inhibit nicotine (5 mg/kg, s.c.)-induced emesis was investigated in Suncus murinus. The anti-emetic action of fentanyl (40 microg/kg, s.c.) was antagonised by the opioid receptor antagonists naltrexone (1 mg/kg, s.c.), naloxone (1 mg/kg, s.c.), M8008 (16S-methylcyprenorphine; 1 mg/kg, s.c.) and MR 2266 (5,9-diethyl-2-(3-furylmethyl)2'-hydroxy-7,7-benzomorphan; 1 mg/kg) but not by naloxone methylbromide (1 mg/kg, s.c.), naloxone methyliodide (1 mg/kg, s.c.), naltrindole (1 mg/kg, s.c.), DIPPA (2-(3,4-dichlorophenyl)-N-methyl-N-[1S)-1-(3-isothiocyanatophenyl)-2-(1- pyrrolidinyl)-ethyl]acetamide; 3 mg/kg, i.p.) or naloxonazine (35 mg/kg, i.p.). This indicates an involvement of mu2-opioid receptors within the brain to mediate the anti-emetic effect of fentanyl. In other studies, naloxone 10-60 mg/kg, s.c. induced dose-related emesis but naltrexone was only emetic at 60 mg/kg, s.c. and naloxone methylbromide failed to induce emesis at doses up to 60 mg/kg, s.c. The emesis induced by a high dose of naloxone 60 mg/kg, s.c. was antagonized by CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine; 3-30 mg/kg, i.p.), 8-OH-DPAT, ((+/-)-8-hydroxy-dipropylaminotetralin; 0.003-0.3 mg/kg, s.c.), buspirone (3 mg/kg, s.c.) and fluphenazine (1-3 mg/kg, i.p.) but not by naltrexone (1-30 mg/kg, s.c.), metoclopramide (0.3-3 mg/kg, i.p.), sulpiride (0.3-3 mg/kg, i.p.), domperidone (0.1-3 mg/kg, i.p.), ondansetron (0.3-3 mg/kg, i.p.), granisetron (0.3-3 mg/kg, i.p.), scopolamine (0.3-3 mg/kg, i.p.) or promethazine (0.3-3 mg/kg, i.p.). The data is discussed in relation to opioid receptor mechanisms moderating emesis and the identification of potential sites of drug action available to inhibit the emetic reflex.     

Adrenalectomy increases bicuculline-induced seizure sensitivity in long-sleep and short-sleep mice

Susceptibility to bicuculline-induced seizure onset and tonus was increased in LS and SS mice after adrenalectomy (ADX). Replacement with 10% corticosterone (CCS) in ADX animals resulted in a return to seizure latencies equal to those of sham-operated (SHAM) mice. In SS mice, dexamethasone (DEX) and cholesterol-control replacement was as effective as 10% CCS in returning seizure thresholds to SHAM values. In LS mice, DEX was only effective at a low bicuculline dose. Within the sham-operated group SS mice were more susceptible to bicuculline-induced seizure onset than LS mice; however, after ADX latencies did not differ between the two lines. These results suggest that seizure thresholds are regulated to some extent by the hypothalamic-pituitary-adrenal (HPA) axis. The effects of ADX on GABA-related seizure activity may also be influenced by genotype, such that genetic differences in GABAA receptor function and adrenocortical responses in LS and SS mice may be responsible for the differential seizure latencies observed in sham-operated mice.     

BUPRENORPHINE AND GASTROINTESTINAL TRANSIT IN RATS: EFFECT OF NALOXONE ON THE BIPHASIC DOSE-RESPONSE CURVE

1. Buprenorphine (0.01-10 mg/kg, subcutaneous [s.c.]) slowed the passage of a charcoal meal along the gastrointestinal tract in rats. The dose-response relationship was U-shaped. 2. When rats were pretreated with naloxone (0.30 mg/kg, s.c.), both the descending and ascending components of the buprenorphine dose-response curve were displaced to the right. 3. Buprenorphine-induced delay of transit was maximal at a dose of 0.10 mg/kg. In rats pretreated with naloxone, a 30-fold higher dose of buprenorphine was required for a comparable peak effect. 4. Moderate-high doses of buprenorphine may be acting on a functionally related binding site which non-competitively inhibits the usual buprenorphine-mu opioid receptor interaction.     

Portal Hypotensive Effects of Tetrandrine and Verapamil in Portal Hypertensive Rats

The portal hypotensive effects of tetrandrine and verapamil (both calcium-channel blockers) were assessed in portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation in Sprague–Dawley rats. Both tetrandrine (4, 8, 16 and 24 mg kg^?1) and verapamil (0.5, 10, 1.5 and 2.0 mg kg^?1) induced dose-dependent decreases of portal venous pressure and mean arterial pressure after intravenous infusion. For example, infusion of tetrandrine (16 mg kg^?1) induced a maximum reduction of portal venous pressure and mean arterial pressure approximately 1 min after the start of infusion. Portal venous pressure decreased from baseline (12.5 mmHg) to 100 mmHg, and mean arterial pressure from baseline (90 mmHg) to 80 mmHg. Heart rate decreased from 250 to 240 beats min^?1. At 24 mg kg^?1, tetrandrine reduced portal venous pressure and mean arterial pressure to 20.3 ± 2.4% and 28.4 ± 1.4% of baseline, respectively. Our results show that both tetrandrine and verapamil induce portal pressure reduction in portal hypertensive animals.     

Blocking of enhanced sensitivity to behavioral effects of naloxone induced by narcotic agonists in rats

The present experiment evaluated whether prior treatment with naloxone could block the sensitization to opiate antagonist induced by single dose administration of pure agonist (morphine) or mixed agonist (buprenorphine). Food deprived male Wistar rats were trained to respond for food on a multiple-trial, fixed-interval 3 min schedule. Reinforcement was contingent upon a response within a 10-s limited hold period following a fixed-interval of 3 min. A trial consisted of three fixed interval of 3 min separated by a 10 min timeout period during which responses were not reinforced. The rate decreasing effects of the opioid antagonist naloxone was determined by cumulative dosing. Pretreatment with morphine (0.3 mg/ kg, SC) and buprenorphine (0.03 mg/kg, SC) resulted in an increase sensitivity to the rate decreasing effect of naloxone compared to saline pretreatment. Administration of naloxone (0.3 mg/kg) 10 min prior to pretreatment doses of buprenorphine (0.03 mg/kg; 1.0 mg/kg) and morphine (0.3 mg/kg) increased sensitization to naloxone. However, greater sensitization was observed at low dose of buprenorphine. The increased sensitivity was partially blocked at high dose of buprenorphine (1.0 mg/ kg) by naloxone pretreatment. These results suggest that the doses of naloxone used to block opioid induced sensitization might be different from those required in animals with normal sensitivity to opioid antagonists. Further agonist-induced sensitization to behavioral effects of opioid antagonist appears to be opioid receptor specific.     

Assessment of the ambulation-increasing effect of ketamine by coadministration with central-acting drugs in mice.

The coadministration of ketamine (12.5 mg/kg, but not 3.1 mg/kg, s.c.) with methamphetamine (2 mg/kg, s.c.), cocaine (10 mg/kg, s.c.), scopolamine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) and MK-801 (0.1 mg/kg, i.p.) significantly enhanced the ambulation-increasing effects. Furthermore, in the coadministration with morphine (10 mg/kg, s.c.) and GBR-12909 (10 mg/kg, i.p.), not only 12.5 mg/kg but also 3.1 mg/kg of ketamine produced a significant enhancement. On the other hand, the ambulation-increasing effect of ketamine (12.5 mg/kg, s.c.) was significantly suppressed by ceruletide (0.01 mg/kg, i.p.), alpha-methyl-p-tyrosine (100 and 300 mg/kg, i.p. x 2), nimodipine (1 and 3 mg/kg, i.p.), haloperidol (0.03 and 0.1 mg/kg, s.c.), a low dose of apomorphine (0.1 mg/kg, s.c.), physostigmine (0.1 mg/kg, s.c.) and N6-(L-2-phenylisopropyl)-adenosine (0.1 mg/kg, s.c.). However, imipramine (20 mg/kg, i.p.), 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (100 mg/kg, s.c.), a high dose of apomorphine (0.5 mg/kg), reserpine (0.3 and 1 mg/kg, s.c.), propranolol (0.3 and 1 mg/kg, s.c.), phenoxybenzamine (3 and 10 mg/kg, s.c.) and naloxone (0.3 and 1 mg/kg, s.c.) scarcely interacted with ketamine. These results suggest that ketamine increases the ambulatory activity in mice by facilitating dopamine release from a newly synthesized pool at the presynaptic level, which is affected by a calcium-dependent mechanism.     

The effect of chronic administration of caffeine on morphine-induced analgesia, tolerance and dependence in mice

Morphine-induced analgesia, and the development of morphine-induced tolerance and dependence was determined in mice which had drunk caffeinated water (1 mg/ml) for 14 days or in mice which had received (-)-N6-(phenylisopropyl)-adenosine (PIA) 1 mg/kg i.p. for 14 days. Analgesia was assessed by the tail flick assay. The development of dependence was assessed by determining the ED50 of naloxone to precipitate withdrawal jumping (3 h after 100 mg/kg morphine pretreatment or 72 h after s.c. implantation of a morphine 75 mg pellet) and by determining the extent of naloxone-precipitated hypothermia in morphine-implanted animals. In mice chronically administered caffeine, the ED50 for morphine-induced analgesia was significantly decreased while the naloxone ED50 for withdrawal jumping increased by 2-fold after both types of morphine pretreatment. In control animals (tap water for 14 days), doses of 1 and 10 mg/kg of naloxone caused significant hypothermia in morphine-implanted animals. Doses of naloxone up to 100 mg/kg did not cause significant hypothermia in morphine-implanted animals which had received chronic caffeine. The development of tolerance was determined by computing the morphine potency ratio for the tail flick assay (tolerant ED50/control ED50). In mice chronically administered caffeine, the potency ratio was decreased significantly in morphine-implanted animals when compared to control. Morphine-induced analgesia, tolerance and dependence was not changed significantly in animals chronically administered PIA. Neither the distribution of morphine to the brain nor the opioid receptor binding parameters for [3H]etorphine and [3H]naltrexone were altered in mice chronically administered caffeine or PIA.(ABSTRACT TRUNCATED AT 250 WORDS)