Chronic exposure to morphine increases corticosteroid-binding globulin

Although it appears that corticosterone may play an important role in determining vulnerability to drugs of abuse, few studies have examined drug effects on factors that affect corticosterone efficacy. Thus, studies were carried out to assess the effects of morphine on corticosteroid-binding globulin (CBG), the major glucocorticoid binder in blood. Since CBG-bound hormone is thought to be physiologically inactive, changes in CBG levels could affect corticosterone action independently of hormone levels per se. We found that morphine caused a marked naltrexone-preventable increase (approximately 160%) in CBG in adult male rats. Elevated levels were seen by three days and were maximal at seven days after morphine pellet (75 mg) implantation. CBG levels remained elevated while morphine was detectable in blood and returned toward normal as the drug cleared from the system. A single morphine pellet was sufficient to induce a marked increase in the concentration of CBG and two or more pellets caused maximal upregulation. Baseline and stress levels of total corticosterone (bound and unbound) were normal after chronic exposure to morphine. However, due to the elevated level of CBG, the amount of free, physiologically active hormone was dramatically reduced. These results suggest that morphine may exert potent effects on corticosterone action that are not revealed by measurement of corticosterone alone. Furthermore, the increase in CBG resulting from chronic exposure to morphine might contribute to the perpetuation of drug use and to adverse effects of drug exposure by impairing normal functions of corticosterone.     

Chronic cadmium exposure alters cocaine self-administration in adult male rats.

Adult male rats (Rattus norvegicus) were exposed to a water supply in the home cage containing 100 ppm cadmium chloride and sodium saccharin (.65% wt/vol; cadmium group) or water containing only the saccharin amendment (group control). On Day 65 of exposure, animals from each group received jugular catheter implants and were subsequently trained over the course of 15 daily 2-hr sessions to self-administer a .25 mg/kg/infusion of cocaine HCl under a fixed ratio 1 schedule. Immediately following acquisition training, the full dose-effect function was determined for all animals by using cocaine doses of .03, .06, .125, .25, .50, and 1.0 mg/kg. Cadmium-exposed animals executed more active (cocaine) lever responses during acquisition training but were not different from controls in depressing a pharmacologically inactive lever. For dose-effect testing, cadmium exposed animals exhibited greater self-administration than controls at the higher doses of cocaine, and there was evidence that the cocaine dose that produced maximum responding was higher in cadmium-exposed than control animals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic exposure to morphine does not alter the neural tissues subserving its acute rewarding properties: Apparent tolerance is overshadowing.

Drug-naive, but not morphine-dependent, rats preferred places paired with morphine (2 mg/kg) over unfamiliar neutral places. Both drug-naive and morphine-dependent rats preferred places paired with higher doses of morphine (20 mg/kg) over unfamiliar places. Lesions of the tegmental pedunculopontine nucleus (TPP) blocked the conditioned place preferences produced by both 2 and 20 mg/kg morphine in drug-naive rats but not the preferences produced by 20 mg/kg morphine in dependent rats. When morphine-dependent animals received withdrawal-alleviating doses of morphine (20 mg/kg) 3.5 hrs before pairing one environment with 2 mg/kg morphine, they showed morphine-conditioned place preferences that were abolished by TPP lesions. The apparent behavioral tolerance to the TPP-mediated rewarding effects may have resulted from overshadowing by separate withdrawal-related motivational mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Saccharin's rewarding, conditioned reinforcing, and memory-improving properties: Mediation by isomorphic or independent processes?

Unconditioned reward and conditioned reinforcing effects may reflect an isomorphic motivational process because increased conditioned reinforcing effects were seen with increased amounts of saccharin consumed in taste and place conditioning. Reinforcing effects in place conditioning leveled off as saccharin unconditioned consumption reached maximum amounts of approximately 140 mg/rat. Posttrial consumption, but not ip injection, of saccharin significantly enhanced conditioned place and taste preferences as well as conditioned taste aversions. Saccharin's memory-improving effects in both aversive and appetitive conditioning suggest a process separate from the reward–reinforcement process. Independent of effects on blood glucose, the motivational property of saccharin's sweet taste undergoes differential central processing to mediate reward–reinforcement vs memory improvement processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ketamine attenuates and reverses morphine tolerance in rodents

BACKGROUND: The development of tolerance complicates the use of morphine to manage persistent pain. N-methyl-D-aspartate receptor antagonists can attenuate or reverse morphine tolerance. The authors studied ketamine's ability to modulate morphine tolerance. METHOD: Tolerance was produced in mice given morphine subcutaneously and was assessed by a cumulative dose-response analysis using the tail-flick test. The ability of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and after morphine to attenuate the development of tolerance was assessed. The ability of 10 mg/kg ketamine to reverse tolerance produced by the subcutaneous implantation of morphine pellets to mice was also assessed. Rats were made tolerant to intraspinal morphine and the effects of the coadministration of 12 micrograms intraspinal ketamine were assessed. RESULTS: Morphine given subcutaneously produced a fivefold increase in the median effective (ED50) dose of morphine, which was dose-dependently attenuated by subcutaneously administered ketamine. A tenfold increase in the morphine ED50 produced by morphine pellets was completely reversed by ketamine given subcutaneously. Intraspinal morphine produced a 46-fold increase in its ED50, which was almost completely attenuated by the coadministration of intraspinal ketamine. CONCLUSIONS: Systemically administered ketamine attenuates and reverses systemically induced morphine tolerance in mice, and intraspinal ketamine attenuates tolerance produced by intraspinal morphine in rats.     

Effects of continuous epidural administration of fentanyl and morphine on postcesarean pain

We studied the effects of continuous epidural administration of fentanyl and morphine with bupivacaine for management of postcesarean pain. Eighteen patients received either bolus epidural administration of fentanyl 100 micrograms or morphine 3 mg with 0.5% bupivacaine 4 ml, followed by continuous infusion of fentanyl 33 micrograms.ml-1 with 0.17% bupivacaine or morphine 0.21 mg.ml-1 with 0.17% bupivacaine for 48 hours, respectively. Pain score was assessed at 0 h, 12h, 24h and 48h after leaving the operating room. Pain score increased significantly and progressively in the fentanyl group. In all cases pruritus was noted. Severe pruritus was observed in the morphine group significantly more than in the fentanyl group. The current results indicate that morphine may be preferable to fentanyl for postcesarean pain control using the present opioid doses.     

A comparison of morphine, pethidine and fentanyl in the postsurgical patient-controlled analgesia environment

Oncogene and tumor suppressor gene mutations are candidate biomarkers for cancer risk assessment and lesion detection. The K-ras oncogene has previously been associated with non-small cell lung cancer (NSCLC), particularly adenocarcinomas in which reported rates of mutation have approached 30-40%. We have analyzed non-malignant lung tissue from patients with lung cancer and primary lung cancers for K-ras gene mutations. Mutations were detected in 32% cancers and 29% non-malignant lung tissue from patients with cancer. The majority of tumors testing positive were adenocarcinoma of the lung. Normal DNA controls, including peripheral blood lymphocytes and normal lung from non-smokers, were negative. The ability to detect genetic alterations in non-malignant lung tissues is consistent with the concept that genetic alterations are involved in field cancerization of the aerodigestive tract.     

Drug exposure and the acquisition and retention of a conditioned taste aversion

Two experiments examined the effects of preexposure and postexposure to a drug on the acquisition and retention of a conditioned taste aversion induced by that drug. Experiment 1 demonstrated that although drug preexposure attenuated a subsequent conditioned aversion, repeated taste-drug pairings reversed the initial attenuation effect and resulted in nearly complete avoidance of consumption. Experiment 2, however, demonstrated that drug postexposure did not alter a previously established conditioned aversion, although the postexposure experiences were effective in attenuating a conditioned aversion to a second novel solution. It was suggested that conditioned aversions are mediated by ACTH and that preexposure to a drug results in tolerance to that drug, yielding a smaller ACTH response and thereby a weaker aversion.     

Delayed extinction attenuates conditioned fear renewal and spontaneous recovery in humans.

This study investigated whether the retention interval after an aversive learning experience influences the return of fear after extinction training. After fear conditioning, participants underwent extinction training either 5 min or 1 day later and in either the same room (same context) or a different room (context shift). The next day, conditioned fear was tested in the original room. When extinction took place immediately, fear renewal was robust and prolonged for context-shift participants, and spontaneous recovery was observed in the same-context participants. Delayed extinction, by contrast, yielded a brief form of fear renewal that reextinguished within the testing session for context-shift participants, and there was no spontaneous recovery in the same-context participants. The authors conclude that the passage of time allows for memory consolidation processes to promote the formation of distinct yet flexible emotional memory traces that confer an ability to recall extinction, even in an alternate context, and minimize the return of fear. Furthermore, immediate extinction can yield spontaneous recovery and prolong fear renewal. These findings have potential implications for ameliorating fear relapse in anxiety disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of morphine with and without fentanyl for epidural analgesia after major abdominal surgery

Expression of fusion proteins between prepro-alpha-factor and somatostatin (SRIF) in yeast, resulted in the correct processing and secretion of the heterologous 14-amino acid SRIF peptide (1). When the chimeric genes were placed under the control of yeast acid phosphatase (PHO5) promoter, significant amount of an unglycosylated form of the fusion precursor molecule accumulated intracellularly, suggesting disruption of an endoplasmic reticulum-mediated function. We report here that the appearance of the precursor is due to an alteration in the three amino terminal residues of the chimera, i.e., Met-Arg-Phe in native prepro-alpha-factor is changed to Met-Phe-Lys in the hybrids. The unglycosylated precursor represents a population of molecules that are disrupted at an early stage of targeting to or translocation across the endoplasmic reticulum membrane. Our data demonstrate that the N-terminus plays an important role in topogenesis. Furthermore, these results show that translocation and glycosylation can be uncoupled from protein synthesis in vivo, and therefore can be posttranslational events in yeast.     

An analysis of the reinforcing properties of food odour.

Evaluated food-odor preference for 24 male albino rats in a double-lever situation where odor presentation and odor-offset were made contingent upon a lever press, or in a noncontingent situation, where no change in stimulus presentation was made contingent upon the lever press. All groups exhibited a significant odor preference, although the odor-onset elicited the greatest preference and the noncontingent situation the least. Results suggest that when odor-stimuli are made response-contingent, the increased probability of responding is due to directing, stimulus-changing, and conditioned-reinforcing properties of the stimulus. (French summary) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of acute smoking exposure on the subsequent reinforcing value of smoking.

The reinforcing value of smoking (i.e., the degree to which a smoker will work to obtain smoking) after varying the magnitude of prior smoke exposure in smokers not trying to quit was examined. Eight men and 8 women participated in 5 sessions involving manipulation of prior exposure to smoking: 0, 2, 6, or 12 puffs after overnight smoking abstinence or ad-lib smoking before the session. After exposure, participants engaged in a computer task involving concurrent schedules of reinforcement for smoke puffs (16% all trials) versus money (4–64%). Only the greatest amount of prior exposure (ad lib) produced a significant reduction in subsequent responding for smoke puffs. No exposure condition significantly increased responding above that for 0 puffs, indicating no priming effect. By contrast, self-report measures of desire to smoke and amount of money participants would pay for a cigarette declined sharply with greater prior exposure. These measures were correlated only weakly with smoke-reinforced responding on the behavioral task, suggesting that subjective versus behavioral measures assess different dimensions of smoking's reward value. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Recovery of ventilatory response to carbon dioxide after thiopentone, morphine and fentanyl in man

Ventilatory responses to CO2 (delta VI/delta PCO2) were measured half, one, two and four hours after infusions of thiopentone, morphine, fentanyl and saline in healthy men in order to test the idea that variation in clinical recovery and control of breathing after anaesthetic drugs are associated with interindividual differences in control measurements of delta VI/delta PCO2. Ventilatory response to CO2 was profoundly reduced one half hour after each drug, in contrast to the observation during air breathing that ventilation and end tidal PCO2 had returned to within 10 per cent of control. Mean delta VI/delta PCO2 increased progressively at one, two, and four hours, returning to near control after thiopentone, but remaining less than 80 per cent of control four hours after morphine and fentanyl. From the regression equations of each ventilatory response, ventilation at PCO2 of 58 and 70 mmHg (VI58 and VI70) were computed to estimate displacement of the response curves by the drugs. Following thiopentone there was no significant change of V158. In contrast ther was a highly siginificant fall of VI58 one half hour after fentanyl (p less than 0.01), with progressive return towards control at one, two, and four hours; similar changes were observed after morphine. For each drug, changes of VI70 were substantially greater than corresponding changes of V158. At all times during these recovery measurements, subjects were conscious and co-operative and, by traditional clinical criteria, were judged to have recovered from the effects of the drugs. Differences between high and low responding subjects were assessed by plotting control measurements against values obtained half and one hour after drugs. No systematic differences were found. These findings suggest that delta VI/delta PCO2 is a sensitive indicator of central nervous activity, but do not support the concepts that individuals with low delta VI/delta PCO2 might be more susceptible to the ventilatory depressant effects of anaesthetic drugs, or that low delta VI/delta PCO2 might be associated with delayed return of spontaneous breathing after general anaesthesia. Plasma thiopentone levels at half, one, and four hours were highly reproducible, in contrast to the wide variation of delta VI/delta PCO2 among subjects in this study. These findings together support the notion that wide variation in clinical recovery from anaesthesia may have a primary physiological basis in addition to variation caused by interindividual differences in drug dosage, biotransformation and excretion.     

Pulmonary effects of chronic exposure to airborne cadmium

In haemoglobinometry grave errors are still being made even though an internationally accepted standardized method is available for the determination of the haemoglobin content of blood. Up to the present only haemiglobincyanide reference solutions have been available on a wide scale to check the measuring stage of the standardized haemiglobincyanide method. These reference solutions are shown to remain stable, under proper storage conditions, for more than 10 years. Concentrated haemoglobin solutions have become available recently, offering the possibility to control the dilution and conversion steps of the haemiglobincyanide method. Such a solution is shown to remain stable, under proper storage conditions, for at least a year. Using both haemiglobincyanide reference solutions and concentrated haemoglobin solutions, as well as having the possibility of checking the cyanide content of the reagent used, an acceptable intra-laboratory control program may now be set up.     

An analysis of the dominant properties of the defensive conditioned reflex

Evaluation of kallikrein-kinin circulatory system was performed via kallikrein, prekallikrein, a1-inhibitor proteinase, a2-macroglobulin, kininase-II and proteolytic activity in 60 patients with chronic persisting hepatitis and incalculous cholecystitis. Two types of kallikrein-kinin system reaction were revealed: hyperkininogenesis in 85% and hypokininogenesis in 15% of all the patients. The problem of fasting diabetics influence on kininogenesis was investigated as well.     

Evaluation of the reinforcing and discriminative stimulus properties of the low-affinity N-methyl-D-aspartate channel blocker memantine

Two experiments were designed to study ultrastructural changes in porcine alveolar macrophages (PAM) inoculated with porcine reproductive and respiratory syndrome (PRRS) virus (experiment 1) and with PRRS virus and Haemophilus parasuis (experiment 2). In both experiments, the viral infectious dose represented a "multiplicity of infection" of 1. Viral infection alone induced minimal ultrastructural changes at this dose, consisting only of an increase in lysosome numbers. Mixed viral and bacterial infection induced the production of greatly increased numbers of phagosomes and phagolysosomes. The PAM were of low efficacy in phagocytizing H. parasuis. PRRS virus infection had only a minimal effect on the phagocytosis of H. parasuis by PAM. It is suggested that the virus induces PAM activation rather than PAM destruction.     

Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons

The mesolimbic dopamine system, which arises in the ventral tegmental area (VTA), is an important neural substrate for opiate reinforcement and addiction. Chronic exposure to opiates is known to produce biochemical adaptations in this brain region. We now show that these adaptations are associated with structural changes in VTA dopamine neurons. Individual VTA neurons in paraformaldehyde-fixed brain sections from control or morphine-treated rats were injected with the fluorescent dye Lucifer yellow. The identity of the injected cells as dopaminergic or nondopaminergic was determined by immunohistochemical labeling of the sections for tyrosine hydroxylase. Chronic morphine treatment resulted in a mean approximately 25% reduction in the area and perimeter of VTA dopamine neurons. This reduction in cell size was prevented by concomitant treatment of rats with naltrexone, an opioid receptor antagonist, as well as by intra-VTA infusion of brain-derived neurotrophic factor. In contrast, chronic morphine treatment did not alter the size of nondopaminergic neurons in the VTA, nor did it affect the total number of dopaminergic neurons in this brain region. The results of these studies provide direct evidence for structural alterations in VTA dopamine neurons as a consequence of chronic opiate exposure, which could contribute to changes in mesolimbic dopamine function associated with addiction.     

Inhibition of reinforcing effects of morphine and naloxone-precipitated opioid withdrawal by novel glycine site and uncompetitive NMDA receptor antagonists

The glycine site (MRZ 2/570 and L-701,324), and uncompetitive (MRZ 2/579) NMDA receptor antagonists inhibited morphine-produced behaviors related to drug-abuse. The expression of morphine dependence was blocked by pretreatment with all three compounds (3-7.5 mg/kg); the effects of glycine/NMDA antagonists were not dose-dependent. Mice which were morphine-free for 3 days still displayed a significant severity of the withdrawal syndrome when challenged again with naloxone. This extinction of a residual morphine dependence was markedly diminished by treatment with similar doses of NMDA receptor antagonists at the test following the wash-out period. The rewarding impact of morphine was investigated in rats using the place preference (CPP) paradigm. All NMDA receptor antagonists (2.5-10 mg/kg) inhibited both the acquisition and expression of morphine-induced CPP. Once established, morphine-induced CPP was observed until 2 weeks after conditioning. NMDA receptor antagonists given for 3 days after the end of conditioning did not influence the extinction of morphine-induced CPP. Microdialysis studies revealed that the behaviorally effective doses of MRZ 2/579 resulted in a brain concentration close to its in vitro potency as an NMDA receptor antagonist. These data suggest that novel glycine site and uncompetitive NMDA receptor antagonists may have therapeutic potential in the treatment of opioid abuse.