Prior Administration Of Naloxone Research Articles

Differential effects of μ and κ opioid analgesics on cerebral glucose utilization in the rat

The autoradiographic 2-deoxy- d-[1- 14C]glucose ([ 14C]2-DG) method was used to map the effects of subcutaneous (s.c.) morphine (8.0 mg/kg), oxymorphone (0.4 mg/kg) and nalbuphine (16.0 mg/kg) on local cerebral glucose utilization (LCGU), and index of local brain function. At the dosages administered, effects of the opioid agonists on LCGU were very restricted. The μ agonists, injected 15 min before [ 14C]2-DG, decreased LCGU in thalamic nuclei, including some of those which have been implicated in somatosensory processing, and in the dorsal tegmental nucleus. Nalbuphine did not produce these effects, but stimulated LCGU in nuclei of the spinal tract of the trigeminal nerve and in the globus pallidus. All of the effects on LCGU were blocked by prior administration of naloxone (1.0 or 10.0 mg/kg, s.c., 5 min before morphine or nalbuphine, respectively). Our findings suggest that different supraspinal mechanisms are involved in the actions of μ vs κ opioids, and indicate that the [ 14C]2-DG procedure might be helpful in elucidating the anatomical areas involved.

The effect of morphine on the potassium evoked release of tritiated 5-hydroxytryptamine from spinal cord slices in the rat

The effect of morphine on the potassium (40 mM) evoked release of exogenous [ 3H]5-HT from slices of the dorsal spinal cord of the rat was studied. The effects of in vitro applied morphine on the slices were compared to those produced by systemic morphine applied to the animals before preparation of the slices. 1. (1) The in vitro application of morphine (10 −6 to 10 −5 M) did not affect the release of [ 3H]5-HT. 2. (2) By contrast, it was observed that the potassium evoked release of [ 3H]5-HT from the slices of the spinal cord of rats which had received 10 mg/kg s.c. of morphine 30 min beforehand was significantly increased. The effect of systemic morphine was dose-dependent (in the range of 1.5–10 mg/kg s.c.) and could be blocked by prior administration of naloxone (1 mg/kg i.m.) 2 min before the morphine. 3. (3) The acute administration of 10 mg/kg s.c. of morphine, which did not induce analgesia in rats rendered tolerant to morphine, did not modify the [ 3H]5-HT release. Higher doses of morphine, which have been shown to restore analgesia in these rats, induced an increase in the release which was significant for a dose of 100 mg/kg s.c. These results demonstrating a specific and dose-dependent increase in the potassium evoked release of [ 3H]5-HT from spinal dorsal cord slices after systemic administration of morophine, emphasize the role of serotonergic systems in such analgesia. The lack of effect of the drug directly applied in vitro favours a supraspinal site of action of the drug and is in good agreement with recent results in the literature.

Stress induced differential intake of various diets and water by rat: The role of the opiate system

The purpose of this study was to explore the effect of acute mild stress (12–48 hour food and water deprivation) and acute severe stress (12 hour food and water deprivation followed by 10 min swim in water at 4°) on the intake of different isocaloric dietary regimes. Each group of experimental animals was given only one particular diet. Rats subjected to mild stress showed very little preference of dietary regimes. When the food intake was measured during 3 hour period, following 48 hours of fasting, animals showed 2 to 3 fold increase in the food and water intake but no particular dietary preference. However, when rats were subjected to severe stress, there was an increase in the food intake of 154% (control diet); 174% (high-carbohydrate diet); 310% (high protein diet) and 423% (high fat diet) compared to animals subjected to mild stress. In terms of the absolute quantity of food, the animals subjected to severe stress ate more high-fat diet than any other diet; the consumption of high fat diet was 142% more than high-protein diet, 180% more than control diet and 258% more than high carbohydrate diet. Animals subjected to severe stress and given high-carbohydrate and high fat diet also showed 80% increase in the water intake. Prior administration of naloxone (1 mg/kg body weight, i.p.) reduced the stress induced increase in the intake of food and water. Naloxone inhibited the intake of high-fat diet more than any other diet. The ability of naloxone to block the increase in the intake of high-fat diet, and the reported increase in the concentration of β-endorphin in the different regions of brain of the animals subjected to the cold swim, suggest that endogenous opioid system in body is activated during stress. An activation of the endogenous opioid system leads to a preferential increase in the intake of palatable foods.

Stimulatory effect of dermorphin, a new synthetic potent opiate-like peptide, on human growth hormone secretion.

Two new related heptapeptides (dermorphins) with potent central and peripheral opiate-like activity have been isolated from the skin of South American frogs, and have been chemically characterized as H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 (dermorphin) and H-Tyr-D-Ala-Phe-Gly-Tyr-Hyp-Ser-NH2 (Hyp6-dermorphin). The response of GH to infusion of a synthetic dermorphin (5.5 micrograms/kg/min for 30 min) was studied in 9 healthy men. Dermorphin (D) significantly increased plasma growth hormone (GH) concentrations. The GH response to D was blunted by prior administration of naloxone, suggesting that D interacts with mu-type opiate receptors. However, the evaluation of the physiological significance of D-induced GH release in humans requires further study.

Effect of morphine on 3H-thymidine incorporation in the subependyma of the rat: an autoradiographic study.

Following morphine treatment, an autoradiographic study investigated the uptake of 3H-thymidine by the subependymal cells in the rat brain. 3H-thymidine was administered subcutaneously to adult, male Sprague-Dawley rats 30 minutes after saline or morphine (19 mg/kg) injection. The animals were sacrified 1 hour after 3H-thymidine administration. In some experiments the opioid antagonist, naloxone, was given alone 45 minutes before 3H-thymidine or 125 minutes before morphine treatment. Three areas of the subependyma were evaluated in terms of the percentage labeled cells and number of grains per nucleus, and a dorsal-to-ventral gradiant was described. Morphine treatment significantly increased the number of 3H-thymidine labeled subependymal cells and number of grains/nucleus within labeled cells. Examination of the distribution of grains/nucleus showed that morphine-treated animals had significantly more cells labeled with 30 or more grains than did saline-injected controls. Prior administration of naloxone blocked the increased 3H-thymidine uptake in morphine-treated animals but had no significant influence on cell proliferation when administered alone. The data are discussed in terms of morphine's possible dual influence on mechanisms which enhance cell transition from G to S phase and/or which accelerate DNA synthesis once these cells have entered the S phase of cell replication.

Modulation of spontaneous seizures in the Mongolian gerbil: Effects of β-endorphin

Intraventricular injection of β-endorphin (0.1–3 μg) into gerbils from the UCLA seizure sensitive strain reduced the incidence and severity of spontaneous epileptiform seizures, both the motor manifestations and the preceding high voltage focal spiking and accompanying seizure activity in the cortical EEG. This “anticonvulsant” effect of β-endorphin was prevented by prior administration of naloxone (1 mg·kg −1 IP). These findings suggest that the endogenous opioid peptide may be involved in the normal suppression of the epileptic diathesis in these animals during the interictal periods.

Changes in the β-endorphin content of discrete hypothalamic nuclei during the estrous cycle of the rat

Concentrations of β-endorphin were measured in discrete brain nuclei of 4-day cycling rats on each day of the estrous cycle. On the afternoon of proestrus β-endorphin levels were significantly higher in median eminence and suprachiasmatic nucleus, and lower in arcuate nucleus, when compared to levels found on other days of the cycle. These changes coincided with the peak of plasma prolactin, which was blocked by prior administration of naloxone.

ANALGESIC EFFECT OF APROTININ IN THE RAT AND ITS INHIBITION BY NALOXONE

Experiments were performed on rats using two analgesimetric tests (tail-flick; hot-plate) before and after injection i.v. of graded doses of aprotinin (12.5, 25.0 and 50 KIU g-1). A dose-related analgesic effect was noted with both tests. Prior administration of naloxone 0.001 mg g-1 i.p. inhibited the analgesic action.

Lack of modulation of pituitary hormone stress response by neural pathways involving opiate receptors.

To evaluate the role of the opiate-like peptidergic pathways in modulating the pituitary hormone response to stress, we measured the GH, PRL, and cortisol responses to hypoglycemia and exercise in normal subjects with and without pretreatment with naloxone, given in the centrally active dose of 0.4 mg iv. Basal serum levels of GH, PRL, and cortisol were not changed significantly by prior naloxone administration. The maximum incremental response of GH to exercise was significantly blunted (13.1 +/- 1.6 vs. 6.0 +/- 1.4; P less than 0.001) by prior naloxone administration. Pretreatment with naloxone did not affect the responses of GH, PRL, or cortisol to hypoglycemia or the PRL response to L-dopa. On the basis of these studies we conclude that the opiate-like peptidergic pathways are not important in the regulation of basal levels of GH, PRL, and cortisol and have only a modest modulating influence on the stress-induced release of the hormones, which may be obscured in the face of severe stress.

Effects of chlorpromazine and naloxone on growth hormone secretion in rats.

The present study was conducted to examine roles of brain monoamines and opioid peptides in growth hormone (GH) secretion in unanesthetized, freely behaving rats. The administration of chlorpromazine (CPZ, 300 microgram/100 g, i.v.), an antagonist of brain monoamines, to rats that were passively immunized with antiserum to somatostatin immediately lowered plasma GH levels and inhibited episodic GH secretion. An intraventricular injection of beta-endorphin (3.5 microgram) stimulated GH secretion. This effect was completely inhibited by the prior administration of naloxone (100 microgram/100 g, i.v.), a specific antagonist of opioid peptides, but not by CPZ. In addition, the administration of naloxone did not inhibit episodic GH secretion. The results suggest that CPZ inhibits episodic GH secretion via a factor(s) other than somatostatin. It is also inferred that brain monoamines, but not opioid peptides, play major roles in the regulation of episodic GH secretion in rats.

Relation of endogenous opioid peptides and morphine to neuroendocrine functions

Morphine and the endogenous opioid peptides (EOP) exert similar effects on the neuroendocrine system. When adminstered acutely, they stimulate growth hormone (GH), prolactin (PRL), and adrenocorticotropin (ACTH) release, and inhibit release of luteinizing hormone (LH), follicle stimulating hormone (FSH),and thyrotropin (TSH). Recent studies indicate that the EOP probably have a physiological role in regulating pituitary hormone secretion. Thus injection of naloxone (opiate antagonist) alone in rats resulted in a rapid fall in serum concentrations of GH and PRL, and a rise in serum LH and FSH, suggesting that the EOP help maintain basal secretion of these hormones. Prior administration of naloxone or naltrexon inhibited stress-induced PRL release, and elevated serum LH in castrated male rats to greater than normal castrate levels. Studies on the mechanisms of action of the EOP and morphine on hormone secretion indicate that they have no direct effect on the pituitary, but act via the hypothalamus. There is no evidence that the EOP or morphine alter the action of the hypothalamic hypophysiotropic hormones on pituitary hormone secretion; they probably act via hypothalamic neurotransmitters to influence release of the hypothalamic hormones into the pituitary portal vessels. Preliminary observations indicate that they may increase serotonin and decrease dopamine metabolism in the hypothalamus, which could account for practically all of their effects on pituitary hormone secretion.

Morphine Decreases Peripheral Vascular Resistance and Increases Capacitance in Man

The response of the human peripheral circulation to morphine in large doeses independent of cardiac and respiratory influences has not been delineated. In 28 patients during cardiopulmonary bypass, alterations of peripheral vascular resistance (PVR) and capacitance in response to rapid arterial injection of morphine, 0.5 mg/kg or 1 mg/kg alone, or preceeded by promethazine, 1 mg/kg, naloxone, 10 mug/kg, or naloxone, 20 mug/kg, were recorded over 15 min at a constant perfusion rate. Both doses of morphine decreased PVR by 46 percent at 2 min, with values returning to control at 9 min. When promethazine preceded morphine, the decrease in PVR after morphine was 25 percent. Naloxone did not alter the response. An increase in capacitance of 600 ml observed 5 min after morphine administration did not revert to control after 15 min, and was unaltered by prior administration of naloxone.

Systemic administration of beta-endorphin: potent hypotensive effect involving a serotonergic pathway.

In normal adult rats anesthetized with urethane, intravenous injections of beta-endorphin (30--150 micrograms kg-1) induced a transient fall of blood pressure followed by a small hypertension and a prolonged hypotension. Prior administration of naloxone completely blocked these effects, whereas naloxone, given 1 hr after beta-endorphin, did not reverse the prolonged depressor phase of the opioid peptide. The effects of beta-endorphin on the arterial blood pressure were greatly reduced in animals pretreated with p-chlorophenylalanine, a specific depletor of serotonin. Moreover, in rats pretreated with potent serotonin antagonists such as cyproheptadine, mianserin, and metergoline, beta-endorphin did not produce a significant hypotension. Furthermore, the depressor effect of beta-endorphin was potentiated by fluoxetine, a specific serotonin uptake inhibitor. These observations suggest the participation of a serotonergic pathway in the action of beta-endorphin on the arterial blood pressure.

Cardiac effects of 1-α-acetylmethadol I. Chronotropic effects in vitro

The drug 1-α-acetylmethadol (LAAM) is a long-acting, orally effective narcotic agonist. It has been proposed as a replacement for methadone in the medical treatment of persons addicted to narcotic analgesics. The purpose of the present investigation was to determine whether or not LAAM possesses chronotropic properties. The results reported here indicate that high concentrations of the major metabolites of the drug (1-α-acetylnormethadol, 1-α-acetyldinormethadol) as well as high concentrations of the parent compound produce significant negative chronotropic effects on isolated right atria of guinea pigs. These effects could not be blocked by the prior administration of naloxone, a narcotic antagonist. LAAM also decreases the positive chronotropic efficacy of norepinephrine.