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Registered: 02/03/03
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Dynorphin, addiction, and the role of salvia.
    #2232767 - 01/10/04 05:45 AM (12 years, 9 months ago)

The following text describes the finding that individuals with higher levels of a Protein called Dynorphin in their brains are less likely to develop an addiction to cocaine. Keep in mind that the active principle of Salvia, Salvinorin A, mimicks the action of Dynorphin in the brain. Both have the ability to bind to the kappa - receptor.

Nature's own antidote to cocaine
Brain opiate may explain why some people are less susceptible to addiction

Some people's brains may harbor their own built-in defense system against the addictive powers of cocaine. According to new research at The Rockefeller University, a naturally occurring brain opiate called dynorphin may, in certain individuals, serve as an antidote to counter the pleasurable, yet dangerous, effects of cocaine.

In the latest Neuropsychiatric Genetics section of the American Journal of Medical Genetics, Mary Jeanne Kreek, M.D., and Rockefeller University colleagues report that people carrying a "high-output" version of the dynorphin gene - one that is thought to result in higher levels of this protein in the brain - may be better protected against cocaine dependence or abuse than those carrying a "low-output" form.

"These results are preliminary, but do suggest that genetic differences in the gene that codes for dynorphin are correlated with individual variations of vulnerability to cocaine abuse," says Kreek, head of the Laboratory of Biology of Addictive Diseases at Rockefeller and senior physician at the Rockefeller Hospital.

"This kind of knowledge is important for the development of both preventative and drug-based treatment strategies for people suffering from cocaine addiction," she adds. Kreek, together with Rockefeller Professor Emeritus Vincent Dole and his late wife and colleague Marie Nyswander, pioneered methadone maintenance programs for the treatment of heroin addicts in the 1960s.

The new genetic association study compared DNA samples from 174 participants, including 83 people who had been previously diagnosed with cocaine dependence or abuse, and 91 "control" individuals with no prior history of any substance abuse. The results suggest that individuals who harbor the high-output form of the dynorphin gene have a significantly lower risk of becoming dependent upon or abusing cocaine than people with the low-output version. The p-value - a measure of statistical significance - for this study was .042 (values of .05 and lower are considered to be significant).

"We were very lucky to have well-characterized subjects for this study," says Andrew Chen, M.D., Ph.D., first author of the study and a research associate at Rockefeller. "The subjects we looked at had been previously diagnosed using very stringent criteria - a fact that supports our findings."

Moreover, previous studies by Kreek and others suggest how this high-output version of the dynorphin gene might protect a person against addiction. Typically, snorting or injecting cocaine triggers a flood of dopamine and other neurotransmitters in the brain, and this, in turn, leads to its characteristic euphoric "high." But, according to the scientists, the brain compensates for this overabundance of dopamine by producing more of the opiate dynorphin, which then reduces levels of dopamine - in essence acting like an antitoxin to neutralize the destructive effects of cocaine. Consequently, higher levels of dynorphin in the brain might translate to increased protection against cocaine.

Because the scientists have demonstrated a possible neurobiological function for this particular genetic variant, it is referred to as a "functional variation."

"Knowing how this genetic variation could potentially modulate the effects of cocaine lends weight to our results," says Chen. "But, on the other hand, our sample size was relatively small, and further studies with more patients are needed to confirm these results."

Dynorphin is a member of the body's natural, or endogenous, opioid system. These molecules, by acting on their corresponding opioid receptors, are responsible for numbing pain, creating feelings of euphoria and increasing energy. They also play a role in the normal functioning of the gastrointestinal and immune systems, as well as modulate how the body deals with stress.

Addictive opiates, which include heroin, morphine and other analgesics such as codeine, are structurally similar to the opioids produced naturally in the body and thus bind to and stimulate the same receptors, subsequently triggering these drugs' well-known effects. Cocaine, on the other hand, acts primarily on the brain's "reward" circuits; it increases levels of dopamine and other neurotransmitters at specific areas of the brain. Yet, research in the last few years has shown that cocaine, like heroin, also acts on the endogenous opioid system - including dynorphin. Studies in rats by Kreek and others have shown that cocaine, while directly inducing a surge in dopamine in the brain, causes a rise in dynorphin levels. Furthermore, Kreek and her colleagues have demonstrated directly in rats and indirectly in humans that administration of dynorphin results in a decrease in the amount of dopamine in the brain.

Together, these studies imply that dynorphin rises after cocaine administration as a means to counteract the effects of cocaine. Under natural circumstances, however, this rise in dynorphin may not be enough to safeguard a person against addiction.

These findings led Kreek and other to speculate that subtle variations, also called polymorphisms, in the gene that instructs brain cells to manufacture dynorphin may explain why some individuals tend to be more resistant to cocaine addiction after experimenting with the drug. Recently, Alexander Zimprich and colleagues at the Otto-von-Guericke University, Magdeburg, Germany have discovered such a variation within this gene.

Zimprich found that a specific piece of the DNA making up this dynorphin gene is present in one, two, three or four copies in different individuals. Furthermore, because this variable region is located in the "promoter" region of the gene (the DNA in front of a gene's coding sequence that controls how much of the protein is made), having more copies of it may lead to higher levels of dynorphin in the brain. Specifically, the researchers demonstrated in cells that genes containing three or four copies of this DNA "repeat" produce more dynorphin than those with one or two.

Kreek's lab has now taken this work one step further by showing a correlation in humans between having three and four copies of the repeat and not being addicted to cocaine. Yet Chen cautions that more studies are imperative in order to confirm their results. In addition to having a small overall sample size, he says that the study did not equally represent each of the major ethnic groups. For example, the Hispanic group contained only 22 individuals.

Ideally, genetic risks should be calculated for each ethnic group separately, in addition to as a whole, to avoid the problems of ethnic or cultural stratification - a phenomenon that occurs when a polymorphism is more frequent in one ethnic population but mistakenly taken to be correlated only with a trait or disease common to that group.

Chen explains, "For example, if you were to look for an association between the trait of using chopsticks and a putative polymorphism without considering that Asian people potentially could harbor this polymorphism in higher frequencies, you might end up concluding that this particular genetic variation causes people in general to use chopsticks.

"Because of this and other limitations of smaller sample sizes, we are planning further studies with more patients."

Cocaine addiction is a serious public health problem around the world and, in particular, the United States. According to the National Household Survey on Drug Abuse, about 1.8 million Americans were chronic cocaine abusers in 1998. Like all addictions, cocaine addiction is a complex disease influenced by many genes, in addition to other behavioral, psychological and environmental factors. However, unlike heroin and other addictive diseases, there are no current pharmaceutical-based treatment programs for cocaine addiction.

Taken from dynorphin.com

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Re: Dynorphin, addiction, and the role of salvia. [Re: heidegger]
    #2278397 - 01/27/04 07:11 PM (12 years, 8 months ago)

great post, maybe it should go to ODD.

Here is another reference:

The main finding of this paper is that Salvinorin A, the active ingredient of the hallucinogenic plant S. divinorum, is a potent and selective KOR agonist. Salvinorin A is a novel nonalkaloid diterpene that has no structural resemblance to any known hallucinogens but does have modest structural homology to enadoline, a selective KOR agonist (Fig. 1 A and C). Salvinorin A thus represents a class of hallucinogens with potent actions at KORs. Because KOR agonists have long been known to have psychotomimetic actions (28), these results imply that the actions of Salvinorin A in humans are mediated, at least in part, via activation of KORs. Additionally, these results imply that KOR-selective antagonists could conceivably represent treatments for diseases in which hallucinations are prominent, including schizophrenia, depression with psychotic features, and the hallucinosis associated with certain dementias (Alzheimer's, Huntington's, and Pick diseases) and certain types of drug abuse (e.g., amphetamine and cocaine psychosis) (29, 30). Previous studies evaluating naltrexone, which is a nonselective opioid antagonist, for the treatment of schizophrenia have yielded equivocal results (31, 32).

Dynorphin was discovered in 1979 by Goldstein et al. (33) and was demonstrated to be an extraordinarily potent endogenous peptide with selectivity for the KOR (34), a GPCR in the opioid receptor family (35). Before the cloning of the KOR, a large amount of behavioral (36, 37), developmental (38, 39), and biochemical (40, 41) data suggested the existence of distinct KORs. Although dynorphin and related peptides represent, in some cases, potent and relatively selective endogenous ligands for the KOR, other types of naturally occurring ligands have heretofore not been identified. The discovery that Salvinorin A is a potent naturally occurring nonalkaloid agonist for the KOR is thus unexpected.

It is now well established that the activation of KORs induces a large number of behavioral effects that include analgesia, sedation, and perceptual distortions. In the past, studies on the precise role of KORs in humans were hampered by the lack of selective agonists, although studies with compounds such as cyclazocine and ketocyclazocine suggested that KOR agonists were psychotomimetic (28). More recently, human studies with the highly selective KOR agonist enadoline (42) indicated that KOR activation induced visual distortions, feelings of unreality, and depersonalization. These effects of enadoline are reminiscent of those previously reported for Salvinorin A (2, 3). Taken together, these results suggest that the KOR/dynorphinergic system functions to modulate human perception and cognition, as might be inferred from detailed anatomical studies of dynorphin peptide distribution studies (43?45).

One of the implications of these results is that KORs or KOR signaling may also be important in the pathogenesis of diseases characterized by perceptual distortions. The most obvious diseases implicated are schizophrenia, dementia, and bipolar disorders, because all are characterized by hallucinations and delusions. Prior studies evaluating KORs in schizophrenia have yielded conflicting results (46?48), whereas one study examining affective disorder was negative (47). On the other hand, two well-controlled studies have demonstrated an up-regulation of KORs in Alzheimer's disease (49, 50), whereas MORs and DORs were down-regulated (50) or unchanged (49).

In conclusion, we report the discovery that Salvinorin A is a potent selective KOR agonist. Salvinorin A thus represents a unique structural class of nonnitrogenous opioid subtype-selective agonists. Additionally, these results suggest that KORs play a prominent role in the regulation of human perception and suggest that KOR antagonists could represent a novel drug class with specific activity in diseases in which alterations in perception are predominant. Finally, these results imply that the KOR/dynorphinergic system functions to modulate human perception and cognition.

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