Opiates analgesic effects

P-Endorphin. A peptide corresponding to the 31 C-terminal amino acids of P-LPH was first discovered in camel pituitary tissue (10). This substance is P-endorphin, which exerts a potent analgesic effect by binding to cell surface receptors in the central nervous system. The sequence of P-endorphin is well conserved across species for the first 25 N-terminal amino acids. Opiates derived from plant sources, eg, heroin, morphine, opium, etc, exert their actions by interacting with the P-endorphin receptor. On a molar basis, this peptide has approximately five times the potency of morphine. Both P-endorphin and ACTH ate cosecreted from the pituitary gland. Whereas the physiologic importance of P-endorphin release into the systemic circulation is not certain, this molecule clearly has been shown to be an important neurotransmitter within the central nervous system. Endorphin has been invaluable as a research tool, but has not been clinically useful due to the avadabihty of plant-derived opiates. 

Chronic opiate treatment results in complex adaptations in opioid receptor signaling. Much has been learned from studies on mechanisms of tolerance to the analgesic effects of opiates. This is a major clinical problem, as it means that ever-escalating doses are required for the treatment of chronic pain. The classic view was that tolerance reflects a decrease in functional opioid receptors via desensitization and internalization. Desensitization occurs when receptors are uncoupled from G proteins as a result of phosphorylation by G-protein-coupled receptor... 

The common side effects of naltrexone are nansea, headache, and dizziness. In addition, naltrexone has the potential for toxic effects on the liver and should not be used in an alcoholic with cirrhosis or other known liver disease. Because it blocks opiate receptors, patients treated with naltrexone are unable to benefit from the analgesic effects of opiates such as codeine or morphine. Naltrexone may increase serum levels of acamprosate in patients taking both medications. 

Only one antagonist is known, naloxone, which is used clinically to treat opiate overdoses and, experimentally, to investigate whether physiological or biochemical actions are opiate-mediated. One example of its use is to support the hypothesis that P-endorphin is responsible for the analgesic effects of acupuncture. Not only does low frequency electroacupuncture increase p-endorphin levels in cerebrospinal fluid but naloxone nullifies the analgesic effect of this treatment. 

Opiate receptors are linked, via the G-protein system, to K+ ion channels and to voltage-gated Ca " ion channels. Binding of the opiates results in opening of ion channels and hyperpolarisation, so that it is more difficult to initiate an action potential, i.e. they behave like inhibitory neurotransmitters (see above). The binding also results in inhibition of the opening of the Ca ion channels in response to depolarisation. That is, both effects are inhibitory on the nervous activity in the brain, which may explain their analgesic effects. 

Nalorphine has less of an analgesic effect than morphine however, it does not have much value as an independent analgesic. It is used as an antagonist to narcotic analgesics. It eliminates suppression of the respiratory center, bradycardia, and vomiting caused by opiate receptor agonists. 

Pharmacology Buprenorphine is a semisynthetic centrally acting opioid analgesic derived from thebaine a 0.3 mg dose is approximately equivalent to 10 mg morphine in analgesic effects. Buprenorphine exerts its analgesic effect via high affinity binding of CNS opiate receptors. 

Meperidine (Schedule II) is a synthetic analgesic with opiate activity. It has 10-20% of the potency of morphine with all of the addictive side effects. It has a rapid onset of action and duration which makes its useful for relieving the pain associated with labor or as a preanesthetic before surgery. Its biotransformation produces normeperidine which has been associated with seizures. It was a botched clandestine attempt to synthesize a meperidine modification which produced the toxic drug that induced parkinson-type destruction of DA neurons in its users. 

Meperidine has replaced morphine to a large extent in medical practice because of the physician s reluctance to use an opiate and the belief that meperidine manifests less undesirable side effects than does morphine. However, both of these assumptions are ill founded. Addiction to meperidine is much less amenable to treatment than is addiction to morphine. Meperidine, similar to morphine and codeine, causes spasm of the upper gastrointestinal tract and typical attacks of biliary colic in biliary tract disease. Meperidine, in doses giving an equal analgesic effect, induces as much respiratory depression as does morphine. Similar to morphine, it also crosses the placental barrier and must therefore be used cautiously in the latter stages of labor. 

Morphine has a strong analgesic effect and has been used for the alleviation of postoperative and cancer pain since antiquity, but its use is now restricted because of its drug dependency. Morphine and its homologues were called opiates after opium, which was extracted from poppy seeds. This class of drugs are now termed opioids. 

Cannabinoids may share at least some common neuronal mechanisms with opioid compounds. Studies of intracellular events associated with ligand binding to either cannabinoid or opiate receptors indicate that these receptors are linked via G proteins to the production of cAMP. Certain studies have also indicated that there may be some interaction between cannabinoid binding sites and opiate receptors in the reward pathway. In addition, there is increasing evidence that cannabinoids interact with opiate systems involved in the perception of pain. In fact, cannabinoids clearly produce analgesic effects in both experimental animals and humans, and of all the potential clinical uses of cannabinoids, the mediation of analgesia has received the most attention. Some evidence also indicates that the cannabinoid receptor system is an analgesic system. 

The morphinomimetic peptides react with the same receptors as the opiate alkaloids and presumably represent the endogenous agonists of these receptors. /i-Endorphin, which represents the functionally active molecule, plays a role in the response of the organism to stress stimuli. The analgesic effect in the body can be traced back to the secretion of /1-endorphin. Accordingly, acupuncture, for example, activates the central nervous endorphin system and causes an increase in the endorphin concentration, leading to the elimination of sensitivity to pain. Presumably there are endorphinergic systems in the central nervous system (CNS) in which the endorphins assume a neuro-modulatory function. 

Whereas these and other beneficial drug interactions are well known and often used in clinical practice, some interactions that are currently considered to be adverse also may be applied therapeutically. For example, the analgesic effects of meperidine and the opiates are augmented by the concurrent administration of MAO inhibitors. This interaction can be used to increase the desirable effects of the analgesics without having to increase the dose. The regimen may have a place in the relief of severe chronic pain in patients with terminal malignant disease. 

O-R agonist [Naloxone-reversed opiate analgesic effects] [analgesic, (piperidine) antinociceptive]... 

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