Cardiovascular effects of naloxone,naltrexone and morphine in the squirrel monkey

Heart rate (HR) and mean arterial blood pressure (BP) were recorded from conscious, chair-restrained squirrel monkeys surgically prepared with chronically indwelling arterial and venous catheters to determine the effects of acute intravenous injections of two opiate antagonists and an agonist. Naloxone (0.3–10.0 mg/kg) or naltrexone (0.3–10.0 mg/kg) had little effect on HR or BP during a 30-minute post-injection period. Morphine (3.0–5.6 mg/kg) produced biphasic effects comprising an initial decrease followed by an increase in HR, and an increase followed by a decrease in BP. Lower morphine doses had lesser effects during a 100-minute post-injection period. Pre-treatment with 0.03 mg/kg naloxone attenuated the depressive effect of morphine on HR and BP, but increases in HR and BP due to morphine were enhanced. Pretreatment with 0.3 mg/kg naloxone prevented morphine-induced decreases in HR and BP, yet increases in HR and BP persisted. In previous behavioral studies, morphine in combination with naloxone similarly increased rates of responding in the squirrel monkey. Together, these data suggest an effect of naloxone that goes beyond mere pharmacological antagonism of the effects of morphine.     

Adrenal dehydrogenases in alloxan diabetic rats following continuous exposure to light

The enzymes delta5-3beta-hydroxysteroid dehydrogenase delta5-3beta-HSD) and glucose-6-phosphate dehydrogenase (G-6-PDH) were demonstrated histochemically in the adrenal cortex of female rat. The activities of these enzymes were increased significantly in the alloxan-treated rats kept in LD (light: darkness) cycles of 10:14 h. Continuous light exposure to diabetic animals appeared to decrease delta5-3beta-HSD and g-6-PDH in comparison to the diabetic rats kept in 10 h illumination. The evidence indicates that suppression of adrenal steroidogenesis in diabetic rats after exposure to continuous light is due to the alteration of pentose phosphate pathway.     

Pulmonary injury in rats following continuous exposure to 60% O2 for 7 days

Morphological, biochemical, and physiological studies were done on rats exposed to 60% O2 for 7 days. This exposure did not induce O2 tolerance but instead caused a significant decrease in survival time of animals subsequently exposed to pure O2. The activity of lung superoxide dismutases and glucose-6-phosphate dehydrogenase were unchanged after exposure to 60% O2. A decrease in lung compliance was suggested by changes in the total lung capacity and in the pressure-volume curves of excised lungs. Ventilation of these animals with large tidal excursion resulted in pulmonary edema. Morphometric analyses revealed a significant decrease in alveolar air volume and an increase in the number of alveolar macrophages. The most significant lesions involved the pulmonary vascular bed. The volume and thickness of the capillary endothelium was decreased. There were focal areas of pericapillary fluid accumulations, and a number of the smaller vessels had perivascular edema. These findings suggest that significant pulmonary injury occurs in rats exposed to 60% O2 and that the primary site of injury is the pulmonary capillary endothelium.     

Effects of morphine or naloxone on kainic acid neurotoxicity.

Intraperitoneal or subcutaneous administration of kainic acid (KA) (5–15 mg/kg) to adult rats included a syndrome of wef wet dog shakes (WDS), convulsions and brain damage. Components of the syndrome were evoked in a dose-related manner with low doses inducing WDS only and progressively higher doses being associated with an increasing incidence of naloxone (4 mg/kg) 5 minutes prior to KA (12 mg/kg) resulted in a moderate reduction in the incidence of WDS, convulsions and brain damage. Administering morphine (5 or 10 mg/kg) 10 minutes prior to KA (7 mg/kg) markedly enhanced the neurotoxicity of KA as was evidenced in an increase in the incidence of convulsions and brain damage from 7% (KA alone) to 100% (morphine + KA). KA, a structural analog of the putative excitatory transmitter glutamate (Glu), is thought to exert its excitotoxic activity through Glu excitatory receptors. Additional studies are needed to elucidate the mechanism by which morphine and naloxone respectively enhance and suppress KA neurotoxicity and to clarify whether interaction of these agents at either opioid or Glu receptors plays a role in such phenomena.     

Neural and behavioral changes in rats following continuous exposure to an odor

Summary Continuous exposure of young rats to the almond-like odor of acetophenone or cyclohexanone for up to 4 months, resulted in distinct but similar patterns of degenerating mitral cells in their olfactory bulbs. Rats favored their exposure odor in olfactory preference tests (Fig. 2) and their acuity for it was not altered (Fig. 3). However, they appeared to exhibit a deficit in detecting a similar but novel odor. The results suggest that the remaining normal mitral cells in the bulbs of these animals are those stimulated by the exposure odor. Cells which show signs of degeneration (Fig. 4) may receive little or no input from the periphery. Controls exposed to a similar but non-odorous environment showed evidence of non-selective mitral cell degeneration. In addition they had a lower acuity for acetophenone and cyclohexanone than animals reared in a normal rat colony (Fig. 3). Anatomical and behavioral data from odor exposed and control groups, suggest that partial regeneration of altered mitral cells may have occurred during a 5 month period following exposure. Overall the results provide further evidence for a topographical projection of the olfactory receptor epithelium onto the olfactory bulb and spatial coding of different odors in the bulb.     

Effects of naloxone and naltrexone on receptive and proceptive behaviors in female rats.

The sexual receptive and proceptive behaviors induced by opiate antagonists, naloxone and naltrexone in estrogen-primed ovariectomized rats were observed under the presence of sexually active males. The females were treated intraperitoneally with naloxone or naltrexone at doses ranging from 0.5 to 4.0 mg/kg and the sexual behavior of females was tested before and after the injection of drug. The results obtained suggest that the opiate antagonists play a role in the regulation of lordosis behavior, but not proceptive behavior in female rats.     

Acclimation of rats following stepwise or direct exposure to heat

The physiological changes in male rats during acclimation were studied following direct or stepwise exposure to heat (32.5 degrees C) in a controlled-environment room. The animals were exposed to each temperature for 10 days beginning at 24.5 degrees C and returning to 24.5 degrees C in the reverse order of initial exposure. Relative humidity of 50 +/- 2% and a 12-h light-dark photoperiod (light from 0900 to 2100 h) were maintained. Physiological changes in metabolic rate (MR), evaporative water loss (EWL), plasma corticosterone, body water turnover, and food and water intake were measured. The results indicate a significantly (P less than 0.001) elevated plasma corticosterone and MR in rats exposed directly to heat from control temperature (24.5 degrees C) but not in those animals exposed stepwise via 29.0 degrees C. All kinetic parameters of water pool changed (P less than 0.01) on direct exposure to heat, whereas rats exposed in a stepwise manner increased only pool turnover. In addition, exposure to experimental temperatures resulted in reduced (P less than 0.05) relative food intake and increased (P less than 0.05) water intake. Compared with the control condition of 24.5 degrees C, EWL was significantly (P less than 0.05) elevated when the animals were exposed either directly or in a stepwise fashion to 32.5 degrees C. These data suggest that the response to elevated temperatures is influenced by the temperature to which the rat is acclimated.     

Translation of muscle mRNA in rats following acute exposure to Pb2+ or Cd2+

The hindleg muscle of rats was studied 2 days following the i.p. administration of 0.5 mg Pb2+ /100 g body wt or 0.12 mg Cd2+ /100 g body wt or both Pb2+ and Cd2+. The incorporation of [14C]leucine into proteins was measured using mRNA obtained from the muscle polysomes. The translatability of this poly(A)+ RNA in a mRNA-dependent reticulocyte lysate was elevated similarly in each of the preparations from heavy metal treated rats compared to control rats. Evidence for increased mRNA activity for glyceraldehyde-3-phosphate dehydrogenase and actin was obtained.     

The late stage following continuous amphetamine administration to rats is correlated with altered dopamine but not serotonin metabolism

In previous experiments rats pretreated with slow-release d-amphetamine (d-Amp) pellets for $\text{4}\text{1}\text{2}$ days, given a 12-hr drug-free period, and then injected with d-Amp have been found to show a behavioral syndrome which has similarities to that induced by acute injections of the hallucinogens LSD and mescaline. The present results indicate that rats administered this same drug regimen have large decreases in Dopamine (DA), dihydroxyphenyl acetic acid (Dopac), and homovanillic acid (HVA) in caudate nucleus, smaller decreases in DA with no changes in Dopac and HVA levels in nucleus accumbens, but no alterations in 5-hydroxytryptamine (5HT) and 5-hydroxyindole acetic acid (5HIAA) levels in caudate, accumbens, brainstem and hippocampus. Increased 5HIAA levels are found in rats sacrificed with pellets intact following 3 days of continuous d-Amp administration, while sleep deprived and in motor stereotypies. The late and hallucinatory stage following continuous d-amp is correlated more closely with alterations in dopamine than of 5HT.     

Analeptic and antianaleptic effects of naloxone and naltrexone in rabbits.

Naloxone (5 mg/kg), but not naltrexone, shortened the duration of anaesthesia in rabbits pretreated with pentobarbital. This analeptic effect was blocked by atropine, but not by methylatropine; it thus appears that a central cholinergic mechanism is involved. In contrast, smaller doses of both naloxone and naltrexone attenuated the arousal property of thyrotropin releasing hormone (TRH). Naloxone, but not naltrexone, also antagonized the analeptic property of d-amphetamine. In conscious animals naloxone potentiated, whereas naltrexone attenuated, the excitatory effects of TRH and d-amphetamine.     

Narcotic antagonist activity of several metabolites of naloxone and naltrexone tested in morphine dependent mice (38558).

A rabbit liver enzyme system was used to produce the 6beta-OH reduced metabolites of naloxone and naltrexone. GC analysis indicated the presence of some 6alpha-OH metabolite in these samples. The narcotic antagonist activity of these 6beta-OH metabolite samples were compared to naloxone, naltrexone and standard 6alpha-OH naltrexone (EN-2260A) using the jumping response of morphine pellet implanted mice. For the naloxone series, the potencies were: Naloxone greater than EN 2265A greater than 6 beta-OH maloxone. For the naltrexone series: Naltrexone greater than EN 2260A greater than beta-OH naltrexone. The low potency of the reduced metabolites the rapid onset of action of the parent compounds militate against the formation of these metabolites contributing substantially to the overall narcotic antagonist action of the parent compounds.     

Early exposure to naloxone increases blood pressure in normotensive and hypertensive rats

Continuous $\text{in}\text{utero}$ and postpartum exposure of SH and WKY rats to naloxone results in a significant increase in their systolic blood pressure relative to respective control animals. After six weeks of age, however, naloxone was no longer effective in sustaining this increase in blood pressure. Chronic exposure to naloxone beginning at three weeks of age failed to produce any significant differences in blood pressure between treated and control animals. Although naloxone has been shown to elevate blood pressure in hypotensive states, this report represents the first example of an increase produced by the narcotic antagonist in the normotensive state.     

Tolerance to morphine in the rat: its prevention by naloxone.

Development of tolerance after a single injection of morphine in the Wistar-Lewis rat can be estimated by the attenuation of the response to a second injection of morphine given three days later. If naloxone is given 35 minutes after the first morphine injection and after the appearance of measurable analgesia, attenuation of the effects of the second morphine injection is not seen. It appears that naloxone blocks the development of tolerance to morphine even if given after the morphine-receptor interaction responsible for analgesia has been initiated. The temporal relationship between the prior injection of morphine and the subsequent administration of naloxone is being explored.     

ACTH and corticosterone response to naloxone and morphine in normal, hypophysectomized and dexamethasone-treated rats

The effect of opiate receptors blocker naloxone on ACTH and corticosterone secretion in normal, dexamethasone-treated and hypophysectomized rats was studied. A dose-related increase in plasma corticosterone level was found at 45 min after s.c. injection of naloxone in a dose range of 0.25-2.0 mg kg-1. The rise in plasma corticosterone was preceded by a slight increase in plasma ACTH. Acute morphine administration in a relatively low dose (6 mg kg-1 s.c.) induced a significant rise in both plasma ACTH and corticosterone levels. Dexamethasone treatment was followed by low basal corticosterone level, by total inhibition of the stress response and response to morphine injection, while the response to ACTH administration was normal. Under these circumstances as well as in rats 6 days after hypophysectomy, naloxone failed to increase plasma corticosterone levels. It is concluded that a direct stimulation of corticosteroid biosynthesis in adrenal cortex is not involved in the mechanism of naloxone-induced activation of pituitary-adrenocortical function.     

Prevention of continuous light-induced anovulation in rats by early exposure to continuous light

Continuous illumination (LL) beginning at 22 days of age caused precocious puberty followed by persistent estrus with anovulation in female offspring originating from mother rats exposed to a 14L:10D light-dark cycle prior to and during pregnancy. However, LL had no deleterious effect on reproductive cycles of offspring reared in LL and originating from mothers exposed to LL prior to and during pregnancy. These rats had a normal onset of puberty in LL, a normal 4-day estrous cycle, a periodic rise of plasma estrogen prior to the periodic appearance of the preovulatory luteinizing hormone (LH) surge, and spontaneous ovulation in LL continued until at least 300 days of age. Also, the female offspring of these rats showed a similar resistance to the deleterious effects of LL on cyclic ovulation. These results support the following interpretation: 1) offspring from mother rats exposed to LL prior to and during pregnancy become insensitive to the deleterious effects of LL on cyclic ovulation, 2) neural elements controlling cyclic release of LH are not totally photoperiod (14L:10D)-dependent, and 3) in the absence of daily 14L:10D signals, an endogenous clock, possibly timed by daily laboratory signals (temperature, noise, taking of vaginal smears), may provide time cues for cyclic LH release.     

Effects of morphine and naloxone on pain sensitivity after radiation injuries in rats

Radiation in doses 150 Gy induces different changes in pain sensitivity in rats by thermal (analgesia) and electrical (hyperalgesia) stimuli. Naloxone (0.1 and 1 mg/kg) and morphine (5 mg/kg) show, that analgesia is realized due to opioid mechanisms.     

Brain levels of morphine in mice following removal of a morphine pellet and naloxone challenge: no evidence for displacement

Male ICR mice were rendered tolerant to and dependent on morphine by subcutaneous implantation of a 75 mg morphine pellet for 72 hours. At 2, 4, and 6 hours after pellet removal groups of 7–10 mice were challenged with ip saline or naloxone and their brain concentrations of morphine estimated by radioimmunoassay (RIA). The brains were prepared for RIA by either organic or inorganic (0.01 N HC1) extraction and in most experiments the two methods were shown to be equivalent with respect to the final concentration of morphine. There was no difference in brain morphine between saline and naloxone (10 mg/kg) treated groups when they were challenged 4 hours after pellet removal and sacrificed 1, 5, 10, 15, 20, 30, 45, and 60 minutes later. In contrast, when the challenge was administered 6 hours after pellet removal the naloxone treated groups has higher concentrations of brain morphine than the saline controls. Brain levels in mice that received 0.10, 1.0, 10, 100 mg/kg naloxone did not differ consistently from saline controls. We found no consistent evidence that naloxone decreases the concentration of morphine in brain homogenates obtained from mice during the initial 6 hours after pellet removal.