Misc The Quotes/Abstracts megathread

[kleinerkiffer]

While skimming through various abstracts about the pharmacology of buprenorphine I came across two interessting things that I wanted to share, but one being too general for the bupe megathread I didn't know where to post it, so I thought a thread like this could come in handy.
Here we can post and dicuss quotes/abstracts about everything related to drugs, but in a more basic language than in Neuroscience and Pharmacology discussion so people without much knowledge in those topics can understand it.



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581407/

Opioid analgesics are used widely for the treatment of moderate to severe pain. The clinical usefulness of these drugs is often hampered by the development of tolerance after chronic treatment. Among others, a proposed mechanism of tolerance is increased activity of the so-called anti-opiate peptides in the brain. Regarding the role of OFQ/N in opioid tolerance, a recent study showed increased levels of OFQ/N in cerebroventricular perfusate, periaqueductal gray and amygdala from morphine-tolerant rats . On this basis, it has been proposed that continuous administration of morphine accelerates the biosynthesis and/or release of OFQ/N to antagonize the effect of morphine, thereby contributing to the phenomenon of tolerance. In support of this notion, intracerebroventricular injection of an antibody raised against OFQ/N partially reversed the expression of morphine tolerance . Moreover, morphine tolerance is partially inhibited in mice lacking the ORL-1 receptor.

This abstract offers a new approach to opioid tolerance development.
Continuous administration of opioids could enhance the biosynthesis and/or release of an amino acid neuropeptide called OFQ/N (Orphanin FQ/Nociceptin). This amino acid neuropeptide binds to a receptor called nociceptin receptor, said receptor plays a role in, amongst others, pain sensation. Activating this receptor can lead to decreased antinociceptive effect from opioids (Paradoxically, supraspinal OFQ/N administration induces hyperalgesia or, at least, blocks the antinociceptive effect of mu, delta and kappa opioid receptor agonists (same source)).
So tolerance could develope by the brain producing/releasing more OFQ/N to counteract the effects of exogenous opioids.
This could lead to a variety of new pain medications

 

[Speed King]

Very excellent post kleinerkiffer. i am looking forward to well put contribution to this thread. I believe you stumbled onto something that is potentially a major HR for opiate/opioid users.

 

[kleinerkiffer]

Interesting abstracts about drugs and epigenetics
www.ncbi.nlm.nih.gov/pubmed/19501473

The term "Epigenetics" refers to DNA and chromatin modifications that persist from one cell division to the next, despite a lack of change in the underlying DNA sequence. The "epigenome" refers to the overall epigenetic state of a cell, and serves as an interface between the environment and the genome. The epigenome is dynamic and responsive to environmental signals not only during development, but also throughout life; and it is becoming increasingly apparent that chemicals can cause changes in gene expression that persist long after exposure has ceased. Here we present the hypothesis that commonly-used pharmaceutical drugs can cause such persistent epigenetic changes. Drugs may alter epigenetic homeostasis by direct or indirect mechanisms. Direct effects may be caused by drugs which affect chromatin architecture or DNA methylation. For example the antihypertensive hydralazine inhibits DNA methylation. An example of an indirectly acting drug is isotretinoin, which has transcription factor activity. A two-tier mechanism is postulated for indirect effects in which acute exposure to a drug influences signaling pathways that may lead to an alteration of transcription factor activity at gene promoters. This stimulation results in the altered expression of receptors, signaling molecules, and other proteins necessary to alter genetic regulatory circuits. With more chronic exposure, cells adapt by an unknown hypothetical process that results in more permanent modifications to DNA methylation and chromatin structure, leading to enduring alteration of a given epigenetic network. Therefore, any epigenetic side-effect caused by a drug may persist after the drug is discontinued. It is further proposed that some iatrogenic diseases such as tardive dyskinesia and drug-induced SLE are epigenetic in nature. If this hypothesis is correct the consequences for modern medicine are profound, since it would imply that our current understanding of pharmacology is an oversimplification. We propose that epigenetic side-effects of pharmaceuticals may be involved in the etiology of heart disease, cancer, neurological and cognitive disorders, obesity, diabetes, infertility, and sexual dysfunction. It is suggested that a systems biology approach employing microarray analyses of gene expression and methylation patterns can lead to a better understanding of long-term side-effects of drugs, and that in the future, epigenetic assays should be incorporated into the safety assessment of all pharmaceutical drugs. This new approach to pharmacology has been termed "phamacoepigenomics", the impact of which may be equal to or greater than that of pharmacogenetics.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864776/

This review demonstrated that there are many consequences for the offspring of parents that were exposed to drugs, even in the absence of direct fetal exposure. The idea that environmental toxins ingested prior to conception by either parent can have such a pronounced impact on the offspring needs further research and should garner more attention. In fact, one study found that the effects of paternal and maternal drug use had an additive effect on offspring's adolescent drug use trajectory rather than an interactive parental effect. This suggests the need for policy change and new campaigns to spread awareness among men and women during adolescence and throughout child bearing years.
The results presented here suggest the intriguing, and potentially alarming, possibility that exposure to drugs of abuse produce transmissible epigenetic changes that result in profound alterations to the physiology and behavior of offspring.

 

[kleinerkiffer]

http://www.ncbi.nlm.nih.gov/pubmed/20026960

Similar to mu opioid receptors, kappa and delta opioid receptors reside in the periphery, the dorsal root ganglion, the spinal cord, and in supraspinal regions associated with pain modulation. Both delta and kappa opioid agonists have been shown to activate pain inhibitory pathways in the central nervous system. Yet, currently there are only a few pharmacologic agents that target kappa receptors, and none that target delta receptors. Spurred by the need for an efficacious analgesic without the unwanted side effects associated with the typical clinical profile of mu opioid agonists, new research has provided insight into why the development of effective kappa and delta opioid receptor agonists has remained elusive thus far, and importantly, how these obstacles may be overcome. For example, for delta opioid agonists to be effective, a state of inflammation may be required as this induces delta opioid receptors to migrate to the surface of neuronal cells and thereby become accessible to delta opioid agonists. Studies have shown that delta opioid agonists can provide relief of inflammatory pain and malignant bone pain. Meanwhile, peripherally restricted kappa opioid agonists have been developed to target kappa opioid receptors located on visceral and somatic afferent nerves for relief of inflammatory, visceral, and neuropathic chronic pain. The recently shown efficacy of these analgesics combined with a possible lower abuse potential and side effect burden than mu opioid receptor agonists makes delta and peripherally restricted kappa opioid receptor agonists promising targets for treating pain.

 

[kleinerkiffer]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698859/

It is also clear that the acute administration of opioid agonists reduces Ca+2 content in synaptic vesicles and synaptosomes, with compensatory upregulation of vesicular Ca+2 content during the development of opiate tolerance

recent in vivo studies show that downregulation does not occur consistently with each and every agonist and may not completely explain tolerance. In light of these findings, it has been suggested that MOR proteins are in fact not downregulated but instead may be desensitized and uncoupled from downstream signaling pathways

it has been shown in vivo that the lack of β-arrestin 2 prevents the desensitization of MOR after chronic morphine treatment and these mice also failed to develop antinociceptive tolerance

 

[kleinerkiffer]

https://books.google.de/books?id=aw...DAA#v=onepage&q=salvinorin A benzoate&f=false
"Salvinorin A was found to be a potent and selective agonist for the kappa opioid receptor. Modification of the C-2 acetate group of salvinorin A by a benzoate results in a compound with affinity and selectifity for the mu opioid receptor termed herkinorin. Herkinorin represents the first non-nitrogenous mu opioid receptor agonist discovered.
Herkinorin was shown to activate the mu opioid receptor without recruitment of ß-arrestin 2 and also without causing internalization of the receptor from cell surface in vitro. Using a rodent model of nociception, herkinorin was shown to be active in vivo. More importantly, because of the unique way herkinorin activates the mu opioid receptor, it does not produce tolerance over a 5 day period and it remains active in animals that have become tolerant to the antinociceptive effects of morphine."

This could change everything

Here's an old thread about it http://www.bluelight.org/vb/threads...-extremely-potent-opioid-w-unusual-properties
Sadly no one tried it afaik