The mu-opioid receptor, which is encoded by the OPRM1 gene, is the primary site of action for opiates with high abuse potential, such as opium and heroin, and may also contribute to the effects of non-opioid drugs, such as cocaine and alcohol. Hutchison, associate professor of psychology at the University of Colorado at Boulder and lead author of the study.
Multiple opiate receptors of brain and spinal cord in opiate addiction.
Thus, it is alcohol's effects on endogenous opioids that act as the gateway through which alcohol may influence this system. Our brains contain proteins, called enkephalins and endorphins, that act like morphine and other opiates derived from the poppy plant. Several researchers have shown that persons with a family history of alcoholism tend to have differences in blood levels of beta-endorphin, a natural opiate hormone, compared to persons without a family history of alcoholism. Children of alcoholics, who are not themselves alcoholics, have lower levels of beta-endorphin than do children of non-alcoholics.
Also, when young adults with a family history of alcoholism drink alcohol, they increase their blood levels of beta-endorphin more than those without a family history of alcoholism. Previous research has shown that the G variant of this gene has a slightly different receptor protein, which causes a big difference in how well the receptor connects with beta-endorphin. For example, the G variant receptor binds three times more tightly than the A variant to beta-endorphin, which means that a nerve cell with the G variant is more greatly affected by beta-endorphin.
The net result is that dopamine cells, which play a role in motivation and reinforcement, become more stimulated. For this study, participants comprised 38 students 20 male, 18 female at the University of Colorado, 21 to 29 years of age, who indicated drinking patterns classified as moderate to heavy. Each received intravenous doses of alcohol that were designed to cause breath alcohol concentration BAC levels of.
There are opioids that have dual agonist and antagonist functions. Table 3. Examples of full agonists include codeine, fentanyl, heroin, hydrocodone, methadone, morphine, and oxycodone. At low doses, both full and partial agonists may provide similar effects to their full agonist cousins.
However, when the dose of partial agonists increases, the analgesic activity will plateau, and further increases in doses will not provide additional relief but may increase the adverse effects. Examples of partial agonists include buprenorphine, butorphanol, and tramadol. Examples include buprenorphine, butorphanol, nalbuphine, and pentazocine. And, some opioids are agonists at 1 or more opioid receptors but also antagonists at other opioid receptors.
The mechanism of action is partial agonist at the mu opioid receptor and full agonist at the kappa opioid receptor. Although pentazocine weakly antagonizes the analgesic effects of full agonists, it also generates incomplete reversal of behavioral depression, cardiovascular, and respiratory induced via morphine and other full agonists.
Nalbuphine has a ceiling effect on respiratory depression at doses greater than 30 mg. Nalbuphine has been reported to reverse respiratory depression but not analgesia of mu-agonists. Buprenorphine has a strong affinity for the mu-receptor causing tight binding and therefore competition at the receptor, displacing other opioids, such as methadone and morphine.
Also, there is incomplete dissociation from the mu-receptor, causing prolonged activity at the receptor. The mu binding affinity of buprenorphine compared with other opioids can be found in Table 5. Of note, buprenorphine has a higher binding affinity compared with naloxone and therefore at higher doses where buprenorphine is most likely to be abused, not readily reversed by naloxone.
It is only at lower doses where there is some competitive binding, and only then should we reasonably expect some reversal by high doses of continuous infusion naloxone. This, of course, begs the question regarding the utility of the combined product, Suboxone. Table 5.
Scientists Just Solved a Major Piece of the Opioid Puzzle
Dynorphins are kappa receptor selective opioid peptides that drive anxiety, stress, and increase desire for opioid use. Further, kappa antagonism has demonstrated antidepressant properties.
Butorphanol is indicated for pain management for patients in which alternative treatment options are ineffective, not tolerated, or inadequate, and is formulated as a nasal spray and injection. Because of the high affinity for kappa receptors, it may cause psychotomimetic effects. However, the duration of respiratory depression is longer, because of predominant mu-mediated physiological responses over the kappa. However, peripheral mu-opioid antagonists do not cross the blood-brain barrier, thus avoiding blockade of centrally mediated analgesia and other centrally mediated opioid agonist effects.
However, Alvimopan is indicated for perioperative management of postoperative ileus to accelerate the time to upper and lower GI recovery following surgery. However, in the story of opioids, opioid antagonists may save lives. Naltrexone is an opioid antagonist that blocks the effects of opioids by competitive binding.
Mu-type opioid receptor - DrugBank
Naltrexone is indicated for alcohol and opioid dependence and useful because its opioid receptor blockade secondarily diminishes dopamine activity that is otherwise enhanced by alcohol. The available formulations are Narcan nasal , Evzio Auto-injector , and solution for injection, the latter of which is frequently administered off label intranasally, by attaching an atomizer to the end of a syringe.
Although the chemistry behind opioids has been outlined, there are other parameters that also need to be factored in to determine individual response. These include age, comorbidities, disease severity, gender, genetics, and weight, all of which may positively or negatively affect the drug response. In addition to the pharmacodynamics outlined herein, many synthetic opioids have additional mechanisms of action, such as noradrenergic reuptake blockade and inhibition of n-methyl-D-aspartase NMDA receptors.
It is therefore important to consider all these variables when making decisions that affect opioid selection or discontinuation. Opioid complications and side effects. Pain Physician. Pharmacology of opioids in the treatment of chronic pain syndromes. Pain physician. Opioid receptors. Annu Rev Biochem. Nelson LS, Olsen D. Goldfrank's Toxicologic Emergencies. Talwin [prescribing information].
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