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Author Topic: Nimodipine and memory loss following Naloxone-induced Morphine withdrawal  (Read 822 times)

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source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326982/

More studies on drugs and memory (and a good way to decode the human memory mechanism), if that shit floats your boat  ::) :o :P :-\ ^-^ so some excerpts follow below:

I have, for so long, wanted to become an "uber-chipper" (not me, a real chipper) by following a smack or M. session with Naloxone to prevent rapid habituation or addiction.

I used Heroin on most weekends for years and never developed a habit. YEARS ! ~ here is a study on something similar but with a twist (using Calcium ion channel modulation.

Other studies of the children of Holocaust survivorys have different amount of "grey matter" when compared to the children of adults who have not been stressed in this most traumatic way.

Memories (experiences or actions) can alter genetic expression and are hereditary. You are what you think and believe (so careful with that axe, Eugene) and so will your children be (and theirs etc.).

The effect of nimodipineWiki on memory loss following naloxone-induced morphine withdrawal in object recognition

Dec 2014

We have previously evaluated the effect of nimodipine (an L-type calcium channel blocker) on memory loss during spontaneous morphine withdrawal.

In the present study the effect of nimodipine on memory loss in naloxone-induced morphine withdrawal mice was investigated.

Mice were made dependent by increasing doses of morphine for three days (hey, lab rats !).

Object recognition task that was used for evaluation of memory performance comprised of three sections: 15 min habitation, 12 min first trial and 5 min test trial.

Naloxone was injected 3 h after the administration of the last dose of morphine. Recognition index was evaluated 20 min after naloxone injection.

Nimodipine was administrated in repeated form (1, 5 and 10 mg/kg) with daily doses of morphine or as a single injection (5 and 10 mg/kg) on the last day.

Both acute and repeated treatments with nimodipine prevented the memory impairment in naloxone-induced morphine withdrawal mice (P<0.05 comparison of acute and repeated treatment data with their corresponding control values).

CorticosteroneWiki concentration was significantly increased in the brain and blood of the mice during withdrawal.

Pretreatment with nimodipine, however, decreased the corticosterone concentration in both brain and blood. The present study showed that nimodipine prevents intense memory loss following naloxone-induced morphine withdrawal.

INTRODUCTION

Morphine, which belongs to a group of drugs known as opiates, is the predominant alkaloid found in Opium poppy plant. It has been used for multiple medical purposes such as reliving pain caused by stroke, surgery, trauma, cancer and kidney stones, as well as the usage in anesthesia.

Morphine is administered to treat cough and pulmonary edema as well. Nonetheless, what nowadays limits the medical usage of morphine is not only physical dependence, but also physical resistance.

Naloxone induced morphine withdrawal may give rise to some symptoms such as severe anxiety, diarrhea, muscular twitches and recognition impairment. Addicted individuals considerably suffer from recognition impairment. EDIT: what habit;)

In spite of intensive research on morphine, the mechanisms involved in recognition impairment have not yet been fully understood. The usage of glucose and insulin can treat recognition impairment caused by administration of a single dose of morphine.

Morley and coworkers reported that naloxone-induced morphine withdrawal activates hypothalamic-pituitary-adrenal axis (HPA) system which is more severe than spontaneous morphine withdrawal.

Ongoing stress results in memory and recognition impairment in humans and animals. This may be attributable to the impact of corticosteroids on memory. High concentration of cortisol in the brain gives rise to neuronal damage and thereby memory loss.

CortisolWiki also causes memory impairment indirectly through excitatory amino acids rather than its direct effect.

Hence, concentration increase of corticosterone in the brain may be plausible explanation for recognition impairment produced subsequent to morphine withdrawal .

In this regard, role of glucocorticoid inhibitorsWiki has also been established.

Chronic use of morphine augments the density of dihydropyridine calcium channels and therefore, their antagonists alleviate symptoms of morphine withdrawal.

Nimodipine is categorized in the group of dihydropyridine calcium blockers which can cross the blood-brain barrier and improves recognition.

Nimodipine ameliorates recognition impairment caused by alcohol withdrawal in animal study.

It appears that nimodipine diminishes cortisol concentration in the brain and improves memory.

Dihydropyridine-sensitive calcium channels serve a role in regulation of cortisol gene expression and their antagonists inhibit induction of c-fos and decline cortisol concentration.

We previously studied the effect of nimodipine on memory loss during spontaneous morphine withdrawal (Vaseghi G, Rabbani M, Hajhashemi V. The effect of nimodipine on memory impairment during spontaneous morphine withdrawal in mice: Corticosterone interaction. Eur J pharmacol. 2012;695:83–87), however the severity of signs and symptoms are different between naloxone and spontaneous withdrawal.

Naloxone induced morphine withdrawal has been reported to be more severe than spontaneous withdrawal (Zelena D, Barna I, Mlynarik M, Gupta OP, Jezova D, Makara GB. Stress symptoms was produced by repeated morphine withdrawal as compared with other chronic stress models in mice. Neuroendocrinology. 2005;81:205–215), therefore, the present study was set out to investigate the effect of nimodipine on recognition impairment caused by naloxone induced morphine withdrawal. The possible interference of this drug in corticosterone function in brain was also assessed in this study.

DISCUSSION

Memory performance, blood and brain corticosterone concentrations after naloxone induced morphine withdrawal in mice were assessed in the present study. The object recognition task provides a rapid assessment of memory performance in mice.

Emotionally arousing learning tasks are generally utilized in animal experiments, unlike memory studies in human subjects. In this method, however, rewarding or aversive stimulation is not used in training; and learning is promoted at relatively low stress or arousal.

Serum corticosterone concentration increased as a result of naloxone precipitated morphine withdrawal in the present study corroborating the findings of a great deal of the previous work in this field.  Our studies show that the morphine impaired memory was lower than that of the control mice.

Acute administration of nimodipine at the dose of 10 mg/kg improved memory performance as can be seen herin. By repeated administration of nimodipine at the dose of 5, 10 mg/kg, memory improved significantly in mice whilst 1 mg/kg of nimodipine had no effects on performance (Fig. ​(Fig.33 and ​and4)4) and ofcourse corticosterone decreased in this dose.

We concluded that memory impairments was at least partially associated with increased brain corticosterone concentrations.

Glucocorticoids affect principally through intracellular receptors, which belong to a nuclear receptor superfamily and regulate the expression of target genes. Hence, the biological effects of the steroids upon tissue are normally slow in onset and are persistent.

Nevertheless, apart from genomic action, glucocorticoids have been shown to exert rapid neural influences through non-genomic mechanisms incorporating membrane-associated receptors.

Noradrenergic mechanisms are activated emotionally arousing stimuli that contribute to modulating memory processes.

It has been shown that various brain preparations increased calcium uptake caused by chronic administration of morphine. EDIT: that's why gabapentinoids / GABAergics are helpful with detoxification pf not just opiods but METH as well.

Yamamoto and coworkers suggested that the increased calcium content rapidly regained normal values following morphine withdrawal.

It has been demonstrated that the number of dihydropyridine-sensitive binding sites in the central nervous system representing voltage-sensitive calcium channels experienced a growth in rats exhibiting signs of morphine withdrawal.

Concurrent treatment of calcium channel antagonists with morphine prevented the naloxone-induced up regulation of [3H] nitrendipine binding sites.

A protective effect of L-type calcium channel blockers against naloxone induced withdrawal have been demonstrated in morphine dependent mice.

Supavilai and coworkers argued that nimodipine, which is known as a dihydropyriddine calcium channel blockers, can cross the blood-brain barrier. It also affects the blood pressure, is selective for the L-subtype high voltage-activated calcium channel.

Apparently, nimodipine reduces cortisol concentration in the brain. Dihydropyridine-sensitive calcium channels are involved in regulation of expression of cortisol gene. Therefore, their antagonists inhibit induction of C-fos and decrease cortisol concentration.

Memory impairment during morphine withdrawal is a complex phenomenon and other mechanisms such as noradrenergic system, cannabinoid receptors activation (EDIT: the old Cannabis memory trashing system that be my pot "funnies"), or brain-derived neurotrophic factor (BDNF) ((* see the abstract of a study at the end of this page) are involved.

CONCLUSION

The present study suggests that impairment of recognition memory after naloxone induced withdrawal at least partially arising from the increase of corticosterone concentration and can be decreased by nimodipine.

The resujts also strongly support the positive role of calcium channel blockers in ameliorating naloxone induced morphine withdrawal syndrome.

the full article can be found at the source link ...

(* from above) BDNF is a member of the NGF family of neurotrophic growth factors

source: https://www.ncbi.nlm.nih.gov/pubmed/22407616

Brain-derived neurotrophic factor and neuropsychiatric disorders.

and excerpt: an abstract

Brain derived neurotrophic factor (BDNFWiki) is the most prevalent growth factor in the central nervous system (CNS).

It is essential for the development of the CNS and for neuronal plasticity as BDNF plays a crucial role in development and plasticity of the brain, it is widely implicated in psychiatric diseases.

This review provides a summary of clinical and preclinical evidence for the involvement of this ubiquitous growth factor in major depressive disorder, schizophrenia, addiction, Rett syndrome, as well as other psychiatric and neurodevelopmental diseases.

In addition, the review includes a discussion of the role of BDNF in the mechanism of action of pharmacological therapies currently used to treat these diseases, such antidepressants and antipsychotics.

The review also covers a critique of experimental therapies such as BDNF mimetics and discusses the value of BDNF as a target for future drug development.

source: https://www.biovendor.com/human-brain-derived-neurotrophic-factor-bdnf-elisa#summary

Summary of Human Brain-derived Neurotrophic Factor (BDNF)

BDNF is a member of the NGF family of neurotrophic growth factors. Like other members of this family, BDNF supports neuron proliferation and survival.

BDNF can bind to a low affinity cell surface receptor called LNGFR, which also binds other neurotrophins such as NGF, NT-3 and NT-4. However, BDNF mediates its neurotrophic properties by signaling through a high affinity cell surface receptor called gp145/trkB.

BDNF is expressed as the C-terminal portion of a 247 amino acid polypeptide precursor, which also contains a signal sequence of 18 amino acid residues and a propeptide of 110 amino acid residues.

--- --- ---

see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697050/ for a discussion on Brain-derived neurotrophic factor and its clinical implications:

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory.

It is widely expressed in the CNS, gut and other tissues.

BDNF binds to its high affinity receptor TrkB (tyrosine kinase B) and activates signal transduction cascades (IRS1/2, PI3K, Akt), crucial for CREB and CBP production, that encode proteins involved in β cell survival.

BDNF and insulin-like growth factor-1 have similar downstream signaling mechanisms incorporating both p-CAMK and MAPK that increase the expression of pro-survival genes.

Brain-derived neurotrophic factor regulates glucose and energy metabolism and prevents exhaustion of β cells.

Decreased levels of BDNF are associated with neurodegenerative diseases with neuronal loss, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease.

Thus, BDNF may be useful in the prevention and management of several diseases including diabetes mellitus.


Note: NeurotrophinsWiki are a family of proteins that induce the survival, development, and function of neurons.

They belong to a class of growth factors, secreted proteins that are capable of signaling particular cells to survive, differentiate, or grow.

see "BDNF/TrkB signaling as an anti-tumor target" at https://www.tandfonline.com/doi/pdf/10.1586/era.11.150
« Last Edit: July 02, 2019, 02:52:25 PM by Chip »
I do not condone or support any illegal activities. All information is for theoretical discussion and wonder.
All activities discussed are considered fictional and hypothetical. Information of all discussion has been derived from online research and in the spirit of personal Freedom.

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