Effects of neurotropin on regional brain noradrenaline metabolism in rats

By measuring levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), in various rat brain regions, we investigated the effects of an extract isolated from vaccinia virus-inoculated and inflamed skin or tissue of rabbits (Neurotropin, NSP), administered acutely or chronically, on regional NA metabolism in stressed and nonstressed rats. An acute administration of NSP at 50 mg/kg significantly elevated MHPG-SO4 levels in the amygdala and cerebral cortex; and 100 mg/kg of the drug significantly increased the metabolite levels in the hypothalamus, amygdala, thalamus, midbrain, cerebral cortex and pons plus medulla oblongata without affecting NA levels. This suggests that acutely injected NSP slightly increases NA release in these brain regions. One hour immobilization stress caused significant increases in MHPG-SO4 levels, which were not affected by pretreatment with either 50 mg/kg or 100 mg/kg of NSP. Chronic injection with NSP daily at either 50 mg/kg or 100 mg/kg for 7 days was without effect on NA metabolism in all brain regions examined. However, increases in MHPG-SO4 levels caused by stress were significantly attenuated in some regions including the hypothalamus, amygdala and midbrain in chronic NSP-treated rats. This indicates that although an acute administration of NSP slightly increases brain NA release, a chronic treatment with NSP rather attenuates increases in NA release caused by immobilization stress in brain regions such as the hypothalamus, amygdala and midbrain. This suggests a possibility that these attenuating effects on stress-induced increases in brain NA release caused by chronic administration of NSP might be related to the stress-reducing or anti-stress properties of NSP.     

Effect of acute ethanol administration on noradrenaline metabolism in brain regions of stressed and nonstressed rats

The effects of ethanol on noradrenaline (NA) metabolism of brain regions in stressed and nonstressed rats were investigated. Male Wistar rats were injected IP with either saline, or ethanol at 0.5 g/kg or 2 g/kg, 5 min before exposure to 1-hr immobilization stress. Levels of NA and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) in various brain regions and plasma corticosterone levels were fluorometrically determined. Immobilization stress caused significant increases in MHPG-SO4 levels in all brain regions examined, i.e., the hypothalamus, amygdala, hippocampus, cerebral cortex and locus coeruleus (LC) region. In nonstressed rats, ethanol significantly increased MHPG-SO4 levels in the hypothalamus, hippocampus and cerebral cortex, but not in the amygdala or in the LC region. In stressed rats, ethanol attenuated stress-induced increases in MHPG-SO4 levels preferentially in the amygdala and LC region, but not in the remaining three regions. Although ethanol per se dose-dependently elevated plasma corticosterone levels in nonstressed rats, ethanol at 2 g/kg attenuated the stress-induced elevation of corticosterone. These results suggest that the attenuating effect of ethanol on stress-induced increases in NA turnover in the amygdala and LC region might be related to the stress-relieving properties of this drug.     

Pentobarbital attenuates stress-induced increases in noradrenaline release in specific brain regions of rats

To examine whether anxiolytic action of drugs acting at the GABA/BZD-chloride channel complex may be related to the brain noradrenergic system, we investigated the effect of pentobarbital, a typical barbiturate which has potent GABA modulating properties, on increased NA release in nine brain regions of stressed rats. Pentobarbital (10 and 25 mg/kg) was injected IP 65 min before sacrifice (5 min before one-hour immobilization stress). Levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), the major metabolite of brain noradrenaline (NA), and of plasma corticosterone, were fluorometrically determined. Pentobarbital treatment by itself increased MHPG-SO4 levels in the thalamus, locus coeruleus (LC) region, midbrain and basal ganglia of nonstressed rats. Stress produced increases in MHPG-SO4 levels in all brain regions examined and elevation of plasma corticosterone levels. Pentobarbital attenuated, in a dose-dependent manner, stress-induced increases in MHPG-SO4 levels in the hypothalamus, thalamus, anterior cerebral cortex, LC region and basal ganglia and also attenuated the stress-induced elevation of plasma corticosterone levels. These data suggest that pentobarbital can attenuate both stress-induced increases in NA release in specific brain regions as well as activation of the hypothalamo-pituitary-adrenocortical system. These attenuating effects may be related to the anxiolytic action of barbiturates.     

Effects of preshock experience on enhancement of rat brain noradrenaline turnover induced by psychological stress

The present study examined alterations of brain noradrenaline (NA) turnover as a function of preshock and psychological stress treatments, by measuring contents of NA metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), in discrete brain regions of male Wistar rats. Psychological stress induced by exposing to the sight, sound and odor of other rats being shocked produced higher levels of MHPG-SO4 in the hypothalamus, amygdala and locus coeruleus (LC) region, as well as higher levels of plasma corticosterone. Preshock experienced rats also showed marked increases of MHPG-SO4 levels in the same regions described above and elevated plasma corticosterone levels when placed but not shocked in the same environment in which the rats had previously received shocks. The effects of psychological stress on brain NA turnover were affected by the animal's shock history preferentially in the hypothalamus and amygdala. These results suggest that: a purely psychological stressor caused acutely enhanced NA turnover in specific brain regions; regional NA activity appeared to be reinstated simply by reexposure to the environment previously associated with shock; preshock experience further intensified the enhancement of amygdaloid NA turnover evoked by psychological stress. An additional experiment, studying the aftereffects of preshock experience, clearly showed that these findings result from sensitization or conditioning to the environment previously paired with shock, and not merely from the aftereffects of the shock per se.     

Differential modification by opioid agents of acutely enhanced noradrenaline release in discrete brain regions

Although immobilization stress-induced increases in MHPG-SO4 level in the hypothalamus, amygdala and thalamus were enhanced by naloxone and attenuated by morphine, both agents failed to exert significant effects upon regional MHPG-SO4 levels in methamphetamine-treated rats. The results indicate that there is a differential modification by opioid agents of acutely enhanced noradrenaline release induced by physiological and by pharmacological manipulations.     

Met-enkephalin, injected during the early phase of stress, attenuates stress-induced increases in noradrenaline release in rat brain regions

By measuring levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), the major metabolite of noradrenaline (NA), we investigated the effects of Met-enkephalin (Met-ENK) ICV injected at three different stages of stress, i.e., 0 min, 5 min, or 10 min after exposure to immobilization stress. Immobilization stress caused significant increases in MHPG-SO4 levels in all brain regions examined, i.e., the hypothalamus, amygdala, thalamus, midbrain, hippocampus and locus coeruleus (LC), which suggests that stress increases NA release in these regions. Met-ENK at a dose of 50 micrograms, injected ICV immediately before stress exposure significantly attenuated stress-induced increases in MHPG-SO4 in the amygdala, thalamus and LC, but did not have such an effect when injected either 5 min or 10 min or 10 min after exposure to stress. Similarly, Met-ENK at 150 micrograms at 0 min significantly attenuated these increases in all brain regions examined, however, it did not do so when given at 5 min or 10 min after stress initiation. The amount of defecation and the weight loss caused by stress were also significantly attenuated by Met-ENK injected but only at 0 min. These results suggest that the attenuating effect of Met-ENK on stress-induced increases in NA release is greatly affected by the time of the peptide administration and that Met-ENK might inhibit stress-induced increases in NA release in these regions by affecting the initial changes induced by stress.     

Stressor predictability and rat brain noradrenaline metabolism

This study examined the effects of stressor predictability on regional rat brain noradrenaline (NA) turnover, by measuring levels of a principal metabolite of NA (3-methoxy-4-hydroxyphenylethyleneglycol sulfate, MHPG-SO4). Male Wistar rats were exposed to one of three shock conditions for 19 hr: nonshock, signalled, and unsignalled shocks. Rats in the shock conditions received shock (1.2 mA intensity, 2 sec duration) on a 2.5 min variable time (VT) either preceded by a 12-sec, 10-W light signal (signal-shock interval of 10 sec) or not preceded by this signal. The tail electrodes for these rats were in series, so that the shock received by all rats was of exactly the same number and duration. After 19 hr in a VT-2.5 min shock session, the rats exposed to unsignalled shock (unpredictable group) showed significantly greater increases in MHPG-SO4 levels in the hypothalamus, amygdala, midbrain, cerebral cortex, thalamus and locus coeruleus, as well as in plasma corticosterone levels. Rats exposed to signalled shock (predictable group) showed significant increases in MHPG-SO4 levels in the first four of these regions, as compared to the nonshocked rats. Moreover, the unpredictably shocked rats exhibited greater elevations in MHPG-SO4 levels in the hypothalamus, amygdala, and thalamus, as well as in plasma corticosterone levels, when compared to the predictably shocked rats. These results are consistent with previous reports showing that unsignalled shock induced extensive somatic effects in comparison to signalled shock. The present study suggests that the presence of a signal attenuates the extent of NA release in some brain regions resulting from irregular inescapable shock stress.     

Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies

A variety of stressful events, including emotional stress, cause a marked increase in noradrenaline release in several brain regions, and especially in the hypothalamus, amygdala and locus coeruleus, in the rat brain. These findings suggest that an increased noradrenaline release could be closely related to the provocation of negative emotions such as anxiety and/or fear. In order to confirm this hypothesis, we carried out several studies. Diazepam, a typical benzodiazepine anxiolytic, significantly attenuated not only the immobilization stress-induced increase in noradrenaline release in the three rat brain regions but also the emotional changes of these animals, and these effects were antagonized by flumazenil, a benzodiazepine antagonist. Naloxone and opioid agents, such as morphine, beta-endorphin and [Met(5)]-enkephalin, significantly enhanced and attenuated the stress-induced increase in noradrenaline release in these regions and the stress-induced emotional change, respectively. Two stressful events which predominantly involve emotional factors, i.e., psychological stress and conditioned fear, caused significant increases in noradrenaline release selectively in these three brain regions and these increases were also significantly attenuated by pretreatment with diazepam in a flumazenil reversible manner. Yohimbine, an alpha(2)-adrenoceptor antagonist which caused a marked increase in noradrenaline release in the several brain regions, had an anxiolytic action in the two behavioral tests involving anxiety, i.e., the conditioned defensive burying test and the modified forced swim test. beta-Carbolines, which possess anxiogenic properties, significantly increased noradrenaline release in the hypothalamus, amygdala and locus coeruleus. Taken together, these findings suggest that the increased release of noradrenaline in the hypothalamus, amygdala and locus coeruleus is, in part, involved in the provocation of anxiety and/or fear in animals exposed to stress, and that the attenuation of this increase by benzodiazepine anxiolytics acting via the benzodiazepine receptor/GABAA receptor/chloride ionophore supramolecular complex may be the basic mechanism of action of these anxiolytic drugs.     

Psychological stress enhances noradrenaline turnover in specific brain regions in rats

Concentrations of noradrenaline (NA) and 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO₄) in the hypothalamus, amygdala, cerebral cortex and pons+medulla oblongata were examined in male Wistar rats exposed to foot-shock or to psychological stress for 1 hour. Animals in the psychological stress group were prevented from receiving foot shock, but were exposed to responses of shocked rats. Foot shocked rats exhibited a significant reduction in NA content and a significant elevation in MHPG-SO₄ level in all brain regions when compared to control rats which were neither shocked nor exposed to shocked rats. Rats exposed to the psychological stress displayed a significant reduction of NA level in the amygdala, significant elevation of MHPG-SO₄ content in the hypothalamus and amygdala, and a moderate elevation of plasma corticosterone level. These results suggest that psychological stress produces mild enhancement of NA release preferentially in the hypothalamus and amygdala; while foot shock stress elicits a more intense response of noradrenergic neurons in more extended brain regions.     

Time-related differences in noradrenaline turnover in rat brain regions by stress

Male Wistar rats were stressed by immobilization from 15 to 180 min and the effect of noradrenaline (NA) and 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO₄) contents in eight discrete brain regions were determined. NA levels significantly decreased and MHPG-SO₄ levels increased in the hypothalamus, amygdala, thalamus, hippocampus, pons+ med.obl. and cerebral cortex. By contrast, the basal ganglia exhibited increases in NA levels and transient decreases in MHPG-SO₄ levels. The midbrain failed to show significant alterations. The most rapid and marked increase in MHPG-SO₄ level was found in the hypothalamus. When rats were exposed to stress after treatment with probenecid 400 mg/kg, the hypothalamus and amygdala showed greater accumulations of MHPG-SO₄ in the early phase of stress, while the pons+ med.obl. and basal ganglia in the later phase. The other regions showed virtually the same accumulations. These results suggest that NA release is enhanced by immobilization in the six regions mentioned above and that response of NA neurons occurs rapidly in the hypothalamus and amygdala but is delayed in other regions.     

Acute morphine effects on regional brain amines, growth hormone and corticosterone.

Morphine sulfate was injected in doses of 5, 10 and 20 mg/kg i.p. to male rats at 3:00 pm. At 4:00 pm, the rats were decapitated and norepinephrine, dopamine and serotonin levels were measured in seven brain regions (cortex, striatum septum, amygdala, hypothalamus, midbrain and pons). Growth hormone and corticosterone levels were assayed from plasma. Saline-injected animals served as controls. The only significant change in brain amine level was an increase in striatal dopamine which occurred after 5 mg/kg morphine. 20 mg/kg caused an increase in plasma corticosterone; lower doses were ineffective. The dose for maximum growth hormone release was 10 mg/kg, although all three doses were effective. It was not possible to relate changes in brain amine levels with these hormonal responses to acute morphine administration.     

Functional magnetic resonance imaging studies of opioid receptor-mediated modulation of noxious-evoked BOLD contrast in rats

Rationale Functional magnetic resonance imaging (fMRI) in rats can non-invasively identify brain regions activated by physiological stimuli and the effects of pharmacological intervention on these responses. Objectives This study was conducted to investigate the effects of systemic administration of the μ-opioid receptor agonist morphine on whole brain functional signal intensity in anaesthetised rats; to investigate whether pre-treatment with the opioid receptor antagonist naloxone blocks the effects of morphine; to determine whether pre-treatment with morphine attenuates noxious-evoked changes in whole brain functional signal intensity. Methods Continuous whole brain fMRI scanning was used to study brain signal intensity prior to, and following, systemic administration of morphine (5 mg/kg, n=7), systemic administration of naloxone (1 mg/kg) and morphine (n=8). Effects of pre-treatment with saline (n=5) or morphine (5 mg/kg, n=5) on formalin (5%, intraplantar)-evoked changes in signal intensity were determined. Data were processed using SMP99 with fixed-effects analysis (p<0.05). Results Morphine produced significant positive bilateral increases in signal intensity in the cingulate cortex, amygdala, thalamus, hypothalamus and PAG (p<0.05), and these effects were blocked by naloxone. Intraplantar injection of formalin produced a significant positive increase in signal intensity in the cingulate cortex, somatosensory cortex, amygdala, thalamus, hypothalamus and PAG (p<0.05). Morphine attenuated formalin-evoked increases in signal intensity in the PAG, amygdala, hypothalamus and cingulate cortex. Conclusion Our data demonstrate that morphine modulates noxious-evoked changes in signal intensity in discrete brain regions. fMRI studies in rats are able to identify specific brain regions involved in the pharmacological modification of physiologically evoked changes in regional brain activation.     

Differences in the effects of morphine on the alpha-methyl-p-tyrosine-induced depletion of dopamine and noradrenaline in various areas of the mouse brain

The effect of morphine on the alpha-methyl-p-tyrosine (alpha MT)-induced depletion of dopamine (DA) and noradrenaline (NA) was studied in various brain areas of male NMRI mice, whose locomotor activity is clearly stimulated by morphine. Morphine (10 mg/kg) accelerated the alpha MT-induced DA depletion in the striatum and in the area "rest of forebrain + midbrain", which contains the limbic dopaminergic neurons, but did not clearly alter it in the hypothalamus. The effects were blocked by naloxone. The enhancement of the striatal DA depletion was attenuated when morphine was given after alpha MT or when morphine dose was increased to 30 mg/kg. The smallest dose of morphine to enhance the alpha MT-induced NA depletion in the forebrain + midbrain area was 3 mg/kg, and in the hypothalamus and the lower brain stem 10 mg/kg. The enhancement of the NA depletion was dose-dependent, occurred whether morphine was given before or after alpha MT, and was blocked by naloxone. Our findings suggest that morphine alters the alpha MT-induced depletion of cerebral DA in mice similarly to what has been reported to occur in rats. In contrast its effects on cerebral NA depletion in mice are clearly different from its effects in rats. The substantial activation of cerebral noradrenergic systems, especially of those in the forebrain + midbrain area, in mice could underly the fact that morphine's predominant behavioural effect in mice is stimulation of motor activity.     

Differences in the Effects of Morphine on the α-Methyl-p-tyrosine-induced Depletion of Dopamine and Noradrenaline in Various Areas of the Mouse Brain

Abstract: The effect of morphine on the α-methyl-p-tyrosine (αMT)-induced depletion of dopamine (DA) and noradrenaline (NA) was studied in various brain areas of male NMRI mice, whose locomotor activity is clearly stimulated by morphine. Morphine (10 mg/kg) accelerated the αMT-induced DA depletion in the striatum and in the area “rest of forebrain + midbrain”, which contains the limbic dopaminergic neurons, but did not clearly alter it in the hypothalamus. The effects were blocked by naloxone. The enhancement of the striatal DA depletion was attenuated when morphine was given after αMT or when morphine dose was increased to 30 mg/kg. The smallest dose of morphine to enhance the αMT-induced NA depletion in the forebrain + midbrain area was 3 mg/kg, and in the hypothalamus and the lower brain stem 10 mg/kg. The enhancement of the NA depletion was dose-dependent, occurred whether morphine was given before or after αMT, and was blocked by naloxone. Our findings suggest that morphine alters the αMT-induced depletion of cerebral DA in mice similarly to what has been reported to occur in rats. In contrast its effects on cerebral NA depletion in mice are clearly different from its effects in rats. The substantial activation of cerebral noradrenergic systems, especially of those in the forebrain + midbrain area, in mice could underly the fact that morphine's predominant behavioural effect in mice is stimulation of motor activity.     

Regional characteristics of stress-induced increases in brain noradrenaline release in rats

Male Wistar rats were exposed to immobilization stress for various periods (1 to 5 hr) with or without an IP injection of probenecid at 400 mg/kg. The regional characteristics of stress-induced increases in noradrenaline (NA) release in the rat brain related to the time-course of stress were demonstrated by measuring levels of the major metabolite of NA, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO₄). Increases in MHPG-SO₄ levels occurred mainly within the first hr of stress in the hypothalamus, amygdala and thalamus, while the peak elevations of the metabolite levels were delayed in the hippocampus, cerebral cortex, pons+medulla oblongata and basal ganglia. According to the accumulation of MHPG-SO₄ during each 1-hr period of stress, regional characteristics of NA release were classified into the following four types based upon regions where the most marked increase in MHPG-SO₄ levels occurs mainly: (1) within the first hr of stress (the hypothalamus, amygdala and thalamus), (2) during the first and second hr (the hippocampus and cerebral cortex), (3) during the third hr (the basal ganglia) and (4) to the same extent from the first to the fourth hr of stress (the pons + medulla oblongata). These results suggest that noradrenergic neurons in different brain regionsrespond differentially to stress and reflect their own characteristic patterns depending upon nature and time-course of the stressor.     

Diazepam-like effects of a fish protein hydrolysate (Gabolysat PC60) on stress responsiveness of the rat pituitary-adrenal system and sympathoadrenal activity

Rationale: Gabolysat PC60 is a fish protein hydrolysate with anxiolytic properties commonly used as a nutritional supplement. Objective: The diazepam-like effects of PC60 on stress responsiveness of the rat pituitary-adrenal system and on sympathoadrenal activity were studied. Methods: The activity of the pituitary-adrenal axis, measured by plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (B) of the sympathoadrenal complex, measured by circulating levels of noradrenaline (NA) and adrenaline (A), and the gamma aminobutyric acid (GABA) content in the hippocampus and the hypothalamus were investigated in male rats which received daily, by an intragastric feeding tube, for 5 days running either diazepam (1 mg/kg) or PC60 (300 or 1200 mg/kg). Controls received only solvent (carboxymethylcellulose 1%). Six hours after the last force-feeding, the rats were subjected to 3 min ether inhalation or 30 min restraint and killed by decapitation 30 min after ether stress or at the end of restraint. Results: Baseline plasma levels of ACTH, B, NA and A were not affected by either diazepam or PC60. Both ether- and restraint-induced release of ACTH, but not B, were similarly and drastically reduced by diazepam and PC60 (1200 mg/kg). Both diazepam and PC60 (1200 mg/kg) deleted restraint-induced NA and A increases. Both treatments also reduced the ether-induced rise of A. Basal levels of GABA were significantly increased in both the hippocampus and the hypothalamus in PC60-treated rats and only in the hippocampus in diazepam-treated ones. In controls, ether inhalation as well as restraint increased GABA content of these two brain structures. In contrast, such stress procedures performed in PC60-treated rats reduced GABA content slightly in the hippocampus but significantly in the hypothalamus. In diazepam-treated rats, GABA content of the hypothalamus was unaffected by stresses but that of the hippocampus was slightly decreased. Conclusions: Present data suggest diazepam-like effects of PC60 on stress responsiveness of the rat pituitary adrenal axis and the sympathoadrenal activity as well as GABA content of the hippocampus and the hypothalamus under resting and stress conditions. These effects of PC60 agree with anxiolytic properties of this nutritional supplement, previously reported in both rats and humans. Received: 27 May 1999 / Final version: 18 October 1999     

Methylphenidate effects on activity-stress gastric lesions and regional brain noradrenaline metabolism in rats

Methylphenidate (5, 10, or 20 mg/kg/day) or saline were administered to rats in the activity-stress ulcer paradigm. Running-wheel activity and food consumption did not differ among groups. Methylphenidate produced dose-related increases in gastric ulcer severity, decreases in hypothalamic noradrenaline (NA) and increases in 3-methoxy-4-hydroxy-phenylethyleneglycol sulfate (MHPG-SO4) in the hypothalamus, amygdala, hippocampus and thalamus. These results differ markedly from the effects seen with a related substance, d-amphetamine, and suggest different mechanisms of action for these drugs.     

Anxiogenic beta-carboline FG 7142 produces activation of noradrenergic neurons in specific brain regions of rats.

By measuring the levels of two major metabolites of rat brain noradrenaline (NA), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG), we investigated the effects of anxiogenic beta-carboline FG 7142, an inverse agonist of benzodiazepine (BZD) receptors, on brain noradrenergic activity of rats. Thirty min after treatment with FG 7142 (15 mg/kg IP), levels of both MHPG and DHPG in the hypothalamus, amygdala and thalamus, but not in the hippocampus and cerebral cortex, significantly increased. These increases were significantly antagonized by pretreatment with BZD receptor antagonist Ro 15-1788 (15 mg/kg, IP). Sixty min after treatment with FG 7142 at the same dose, significant increases in both metabolite levels occurred in the hypothalamus, amygdala, thalamus and cerebral cortex, and increases in MHPG levels only were observed in the hippocampus. These increases were significantly blocked by pretreatment with alpha 2-adrenoreceptor agonist clonidine (100 microgram/kg, IP). The present findings suggest that FG 7142 can produce increases in brain noradrenergic activity in specific brain regions by interacting with BZD receptors, and may support the hypothesis that hyperactivity of brain noradrenergic systems may be one neural mechanism in provocation of aversive emotional changes (anxiety, fear or panic).     

The effect of stress and adrenalectomy on morphine analgesia and naloxone potency in mice.

Pretreatment of mice with a single injection of corticosterone increased the potency of naloxone in antagonising the antinociceptive effect of morphine measured 3 h later. Pretreatment with morphine also induced a dose-dependent increase in naloxone potency. Co-administration of corticosterone with a low dose of morphine further augmented the potency of naloxone, but in combination with a higher dose of morphine it failed to cause any further potentiation of naloxone potency. Restraint stress for 1 h also caused an increased in naloxone potency when tested 3 h later, and this was further enhanced when tacrine 5.0 mg/kg was administered immediately after stress. Administration of atropine sulphate 2.0 mg/kg s.c. immediately before restraint abolished the effect of stress in potentiating the naloxone potency. Adrenalectomy sensitised mice to the antinociceptive effect of morphine. Although adrenalectomy only partially interfered with the development of increased naloxone potency after pretreatment with morphine, the augmenting effect of tacrine on naloxone potency was completely abolished. Adrenalectomy did not alter the incidence of jumping precipitated by naloxone in morphine-pretreated mice. Both restraint and corticosterone reduced the withdrawal jumping. It is concluded that the stress component of morphine is only partly responsible for the induction of increase in naloxone potency. There is an apparent interaction between central cholinergic mechanisms and stress in the induction of this increased naloxone potency. The phenomenon of increased naloxone antagonism may not be related to the development of acute dependence on morphine.     

Effects of acute morphine administration on noradrenaline turnover and metabolism in various brain parts of control and handled rats

The main purpose of these experiments was to study whether the morphine-induced changes in cerebral noradrenaline (NA) turnover differ between various brain areas of male Wistar rats assessed by the alpha-methyl-p-tyrosine (alpha MT)-induced NA depletion. The effects of repeated saline injections (20 days) on the morphine-induced changes in NA and also in free and sulphated 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG) concentrations were studied. 5 to 40 mg/kg of morphine reduced the alpha MT-induced NA depletion in the cortical hemispheres, while 40 mg/kg of morphine enhanced it in the lower brain stem. 10 mg/kg of morphine lowered the NA concentration in limbic forebrain and hypothalamus and increased it in the cortical areas. It also elevated the MOPEG concentrations in all brain parts with the sole exception of sulphated MOPEG in the cortical hemispheres. Naltrexone antagonized the morphine-induced changes in NA turnover and MOPEG concentrations. The only significant handling-induced change was the elevation of NA concentrations in the hypothalamus. The increasing effect of morphine on the sulphated MOPEG concentration in the prefrontal cortex and the lower brain stem was attenuated in handled rats. In conclusion, these findings show that, the response of cortical NA neurones to acute morphine administration is retardation of turnover rather than activation which occurs most notably in the lower brain stem. Furthermore, the responses are modified by previous exposure of rats to handling.