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At least 19 recordsLinked to original sources
PubMed1978

Effects of furosemide and spironolactone on the behavior of morphine-tolerant rats.

In morphine-tolerant rats, a reappearance of morphine catalepsy and a disappearance of the turning behavior characteristic of brain-lesioned tolerant animals were observed under the influence of furosemide and spironolactone. The administration of spironolactone together with daily morphine treatment resulted first in an intensification of the morphine symptoms as measured by catalepsy and a retarded appearance of tolerance, typically characterized by a shift from catalepsy to turning movements in animals with single-sided brain lesions. Nontoxic doses of spironolactone raised the sensitivity of morphine-tolerant rats so that previously tolarated morphine doses become lethal.

Animals↗
PubMed1978

Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking solutions.

Rats were housed on a cabinet designed to control their access to water or morphine solutions. They were trained to drink all of their fluid as morphine solutions or tap water during 5-minute access periods scheduled at 2 A.M., 8 A.M., 2 P.M. and 8 P.M. On this schedule, the morphine drinking rats consumed an average of 29, 27, 21 and 23% of their total daily fluid during the four respective access periods. The rats that had access to the 0.05% morphine solution drank an average of 53 mg/kg/day of morphine. Separate groups of rats were tested for morphine tolerance and dependence at 4-day intervals. Tolerance to the analgesic effect of challenge doses of morphine (3, 6 and 9 mg/kg) was first detected after 10 days of morphine drinking and reached a plateau after 18 days. Withdrawal scores for rats injected with 0.3 or 3 mg/kg of naloxone reached a plateau between 14 and 18 days of morphine drinking, whereas the scores of rats given 0.03 mg/kg were still increasing after 26 days of drinking. Plasma levels of morphine ranged between 167 and 300 ng/ml in blood samples collected 1 hour after each access period on the 18th day of morphine drinking. Six hours after the 8 A.M. access period, the levels of morphine in the plasma had decreased to 50% of the levels detected at 1 hour after the access period. Ninety percent of the rats accepted the morphine solutions and drank regularly for the 26 days the solutions were offered. They remained healthy throughout this period and, except for the fact that they gained 11% less body weight over the 26 days, they were visibly indistinguishable from the water drinking control rats.

Animals↗
PubMed1976

Morphine tolerance and physical dependence: influence of cholinergic agonists and antagonists.

The effects of centrally acting agents which alter cholinergic activity were assessed in mice rendered tolerant to and dependent on morphine (M mice) and in naive mice (N mice). In both N and M mice, physostigmine potentiated morphine analgesia slightly, and this action was blocked by atropine and scopolamine. When administered 10 min before naloxone in dependent mice atropine enhanced precipitated withdrawal jumping; when given 30 min before naloxone, atropine produced an inhibition of the response. Physostigmine abd oxotremorine greatly inhibited the jumping response, while echothiophate had no effect. The inhibitory effect of physostigmine on naloxone precipitated withdrawal jumpimg was reversed by atropine and scopolamine but atropine did not alter morphine tolerance and dependence development. Brain acetylcholine (ACh) levels in both N and M mice were increased by physostigmine, the increase being greater in M mice. This increase was blocked by prior administration of atropine or scopolamine. When atropine was administered to M mice 10 min before sacrifice, brain AC-h levels decreased. However, when brain ACh levels were determined 30 min after atropine, no change was found. It was concluded that ACh does not play a major direct role in the development of tolerance and dependence, but that ACh is involved in the manifestations of acute morphine effects and in some of the withdrawal signs in the dependent state.

Acetylcholine↗
PubMed1976

Effect of pargyline on morphine tolerance and physical dependence development in mice.

The effects of single and repeated pargyline administration on morphine antinociception in both naive and morphine-tolerant mice and on naloxone-precipitated withdrawal in morphine tolerant-dependent animals were investigated. Adult, male Swiss-Webster mice were rendered tolerant to and dependent on morphine by the s.c. pellet implantion technique. Morphine analgesia, as assessed by the tail-flick antinociceptive test, was potentiated in tolerant animals by acute adminstration of pargyline but antagonized by repeated pargyline administration; pargyline produced similar effects in non-tolerant mice and to the same relative degree. Repeated pargyline treatment during morphine pellet implantation enhanced the withdrawal jumping response precipitated by naloxone in dependent mice. Pargyline also, after a single injection, exacerbated jumping in mice undergoing abrupt withdrawal. Neither acute nor chronic pargyline administration altered the brain distribution of injected morphine in non-tolerant mice. It was concluded that pargyline may modify acute morphine actions and withdrawal without materially altering the process(es) involved in the development of tolerance and physical dependence.

Animals↗
PubMed1977

Morphine tolerance acquisition as an associative process.

The results of several experiments supported the proposal that morphine analgesic tolerance is a manifestation of an association between the drug administration ritual and the systemic effects of the drug: (a) Presenting environmental cues previously associated with morphine, but without the drug, attenuated established tolerance (i.e., morphine tolerance can be extinguished), (b) repeated presentations of the morphine administration procedure, prior to its pairing with the opiate, retarded the acquisition of tolerance (i.e., morphine tolerance is subject to "latent inhibition"), and (c) placebo sessions interspersed between morphine sessions deleteriously affected the development of tolerance (i.e., morphine tolerance is subject to the decremental effects of partial reinforcement). These findings appear inexplicable by most traditional theories of tolerance, which do not emphasize the role of drug-associated environmental cues in the development of tolerance. Additionally, it is suggested that the conditioning analysis of tolerance is congenial with a current view of habituation, and there may be a similar associative basis for the response decrement to both endogenous and exogenous iterative stimulation.

Animals↗
PubMed1978

Pavlovian conditioning analysis of morphine tolerance.

It has been demonstrated that many conditional responses to a variety of drugs are opposite in direction to the unconditional effects of the drug, and the conditioning analysis of morphine tolerance emphasizes the fact that subjects with a history of morphine administration display morphine-compensatory conditional responses when confronted with the usual administration procedure but without the drug. Thus, when the drug is presented in the context of the usual administration cues, these conditional morphine-compensatory responses would be expected to attenuate the drug-induced unconditional responses, thereby decreasing the observed response to the drug. Research has been summarized which supports this compensatory conditioning model of tolerance by demonstrating that the display of tolerance is specific to the environment in which the drug has been previously administered. Further evidence supporting this theory of tolerance has been provided by studies establishing that extinction, partial reinforcement, and latent inhibition--non-pharmacological manipulations known to be effective in generally affecting the display of conditional responses--similarly affect the display of morphine tolerance. Additional research has suggested many parallels between learning and morphine tolerance: Both processes exhibit great retention, both are disrupted by electroconvulsive shock and frontal cortical stimulation, both are retarded by inhibitors of protein synthesis, and both are facilitated by antagonists of these metabolic inhibitors.

Animals↗
PubMed1977

The effects of 4-imidazolyl-3-amino-2-butanone (McN-A-1293), a specific histidine decarboxylase inhibitor, on the expression of morphine tolerance and physical dependence in mice.

McN-A-1293, a specific histidine decarboxylase inhibitor administered intracisternally in the 'withdrawal' phase, significantly suppressed the expression of morphine tolerance. Severity of withdrawal, assessed by percentage body weight loss, was significantly enhanced although incidence of jumping was unaltered. The opposite effects of this compound on morphine tolerance and withdrawal suggest that tolerance and physical dependence are based on different underlying mechanisms.

Animals↗
PubMed1976

The effects of L-histidine and of specific histamine receptor agonists, on the expression of morphine tolerance and physical dependence in mice.

The effects of L-histidine, and of the specific histamine receptor agonists 2-methylhistamine and 4-methylhistamine, on the expression of morphine tolerance and physical dependence have been studied in mice. These agents were administered during the "withdrawal" phase of development. All of them significantly increased tolerance but reduced the degree of physical dependence. The effects of 2-methylhistamine, which has predominantly H1-receptor activity, were completely abolished by the prior administration of the H1-antagonist mepyramine. The H2-antagonist metiamide, on the other hand, did not alter the action of 2-methylhistamine on physical dependence, though tolerance was restored to its original level. The effects of 4-methylhistamine, which is a specific H2-receptor agonist, were inhibited by metiamide, but mepyramine was unable to reverse the actions of this agonist. The effects of L-histidine, the major precursor of brain histamine, were unaltered by mepyramine, but partially inhibited by metiamide. These experimental findings are discussed in detail, and are considered to give further support to the view that histamine is implicated in some way in the mechanisms of the "withdrawal" phase of morphine tolerance and physical dependence in mice, with H2-receptors probably playing the more important role.

Animals↗
PubMed1978

Time course of effects of morphine on hypothalamic content of LHRH and serum testosterone and LH levels of morphine-tolerant and nontolerant male rats.

Time course of the effects of morphine on the hypothalamic content of LHRH in both nontolerant and morphine-tolerant male rats was investigated in relation to the temporal changes of serum testosterone and LH levels. The hypothalamic LHRH content of the nontolerant rats was increased 8 hr after the administration of morphine (100 mg/kg) when serum testosterone levels were depressed. The LHRH content of the tolerant rats was decreased during withdrawal of morphine for 48 hr when the lowered serum testosterone and LH levels had returned to within the control levels. Although the hypothalamic LHRH content does not necessarily reflect the release of LHRH, these results are in favour of the hypothesis that the release of hypothalamic LHRH is inhibited by the administration of morphine and is restored by the withdrawal of the narcotic.

Animals↗
PubMed1978

Effects of morphine on the serum prolactin levels of morphine-tolerant and nontolerant male rats and of the in vitro release of pituitary prolactin.

Morphine increased the serum prolactin (PRL) levels of male rats in a dose response manner. This effect was abolished by naloxone and apomorphine, but was not affected by diphenhydramine. The increase in the serum PRL levels by haloperidol was abolished by apomorphine, but not by naloxone. Repeated administrations of increasing doses of morphine attenuated the response of serum PRL to morphine. Naloxone did not alter the serum PRL levels of morphine-tolerant rats, while it precipitated full withdrawal signs on these rats. Although neither haloperidol nor morphine increased the release of PRL from the isolated anterior pituitary, haloperidol, but not morphine, reversed the inhibition by dopamine of the in vitro release of pituitary PRL. These results indicate that tolerance develops regarding the effect of morphine with a resulting increase in the serum PRL levels, abstinence precipitated by naloxone has no effect on the serum PRL levels, the mechanism of morphine involved in increase in the serum PRL is different from that of haloperidol as the effect of haloperidol is not antagonized by naloxone and morphine does not antagonize the effect of dopamine which inhibits the release of PRL from the anterior pituitary in vitro.

Animals↗
PubMed1978

The effects of divalent ions on morphine analgesia and abstinence syndrome in morphine-tolerant and -dependent mice.

Intracerebral administration of copper sulfate potentiated morphine analgesia in morphine-tolerant and -dependent mice, but copper failed to affect other abstinence signs. When abstinence was precipitated with a partial antagonist, nalorphine, stereotyped jumping was not inhibited by either calcium or copper. These modifications of narcotic effects by copper were produced without alterations in the brain disposition of morphine. Total radioactivity in the brain following radioactive naloxone administration was also not altered.

Analgesia↗
PubMed2025

Network pharmacology approach to unveiling the mechanism of berberine in the amelioration of morphine tolerance.

OBJECTIVE: To investigate the mechanism underlying the effect of the Huanglian decoction (, HLD) on morphine tolerance (MT), using network pharmacology, and to verify these mechanisms in vitro and in vivo. METHODS: Available biological data on each drug in the HLD were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The target proteins of MT were retrieved from the GeneCards, PharmGkb, Therapeutic Target Database, DrugBank, and Online Mendelian Inheritance in Man databases. Information regarding MT and the drug targets was compared to obtain overlapping elements. This information was imported into the Search Tool for the Retrieval of Interacting Genes/Proteins platform to obtain a protein-protein interaction network diagram. Then, a "component-target" network diagram was constructed using screened drug components and target information, viaCytoscape (Institute for Systems Biology, Seattle, WA, USA). The database for annotation, visualization, and integrated discovery was used for Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathways analyses. Pathway information predicted by network pharmacology was verified using animal studies and cell experiments. RESULTS: Network pharmacology analysis identified 22 active compounds of HLD and revealed that HLD partially ameliorated MT by modulating inflammatory, apoptosis, and nuclear factor kappa B (NF-κB) signaling pathways. Berberine (BBR), one of the main components of HLD, inhibited the development of MT in mice. BBR reduced cell viability while increasing B-cell lymphoma 2 (Bcl-2) protein expression and decreasing CD86, NF-κB, Bax, and Caspase-3 protein expression in brain vascular 2 (BV2) mcroglia cells treated with morphine. Additionally, BBR contributed to a reduction in pro-inflammatory cytokine release and apoptotic cell number. CONCLUSIONS: BBR, a key component of HLD, effectively suppressed microglial activation and neuro-inflammation by regulating the NF-κB and apoptosis signaling pathways, thereby delaying MT. This study offers a novel approach to enhance the clinical analgesic efficacy of morphine.

Berberine↗
PubMed1979

The effect of morphine tolerance on the incorporation of 3H-leucine into proteins of rat synaptic membranes.

The rate of incorporation of 3H-leucine into proteins of the synaptic junctional and nonjunctional membranes and synaptic vesicles of rat brain has been examined in control and morphine-tolerant rats. There are no discernible differences between control and tolerant animals in amount of protein as measured by densitometric tracings of dye-stained proteins separated by acrylamide gel electrophoresis from the three membrane fractions of whole brain areas. However, there are differences in the turnover of membrane protein: three vesicle protein bands and one junctional-membrane protein band are significantly more highly labeled, and one junctional-membrane protein is significantly less highly labeled by 3H-leucine in samples from tolerant rats. Of these, the two junctional-membrane proteins can be tentatively identified as components of the post synaptic densities, and one of the vesicle proteins as tubulin.

Animals↗
PubMed1978

Alteration of brain chromatin and nuclear synthetic activity in morphine-tolerant rats.

3H-UTP incorporation by endogenous RNA-polymerase of intact, isolated rat brain nuclei was enhanced by chronic morphine treatment. Analgesic tolerance using the hot-plate assay was also evident. Fractionation proflies for brain chromatin on hydroxylapatite from morphine and vehicle-treated rats was different. These results suggest that morphine-tolerance in the rat may be accompanied by enhanced nuclear synthesis of a new species of RNA.

Analgesia↗
PubMed1975

Evidence from rats that morphine tolerance is a learned response.

It is proposed that the direct analgesic effect of morphine becomes attenuated over the course of successive administrations of the narcotic by a conditioned, compensatory, hyperalgesic response elicited by the administration procedure, the net result being analgesic tolerance. Using the "hot plate" analgesia assessment situation with rats, this conditioning view of tolerance is supported by several findings: (a) It is necessary to have reliable environmental cues predicting the systemic effects of morphine if tolerance is to be observed, (b) a hyperalgesic conditioned response may be observed in morphine-tolerant subjects when drug administration cues are followed by a placebo, and (c) merely by repeatedly presenting environmental cues previously associated with morphine (but now presented with a placebo), morphine tolerance can be extinguished.

Analgesics, Opioid↗
PubMed1978

Effects of Met-enkephalin on body temperature of normal and morphine-tolerant rats.

The endogenous opioid met-enkephalin intraventricularly adminstered to the rat at the dose of 100 microgram raised rectal temperature, whereas 400 microgram of the pentapeptide caused a diphasic effect, i.e., hypothermia followed by hyperthermia. Met-enkephalin was ineffective when administered i.p. The effects on temperature were substantially similar to those elicited, for both routes of administration, by morphine, which may either raise or lower rat temperature depending on the dose. More naloxone was required to antagonize thermic effects of met-enkephalin than morphine. Finally, there was a lack of effects on temperature for met-enkephalin centrally administered to morphine-tolerant animals, thus providing further evidence, in vivo, of cross tolerance between opiates and naturally occurring ligands of opiate receptors.

Animals↗