Morphine receptor interactions

Narcotic analgesic. A drug that alleviates pain by interacting with the morphine receptor. 

Receptor interactions are those where two chemicals both interact with the same receptor to change (usually decrease) the toxic effect of the combination. For example, naloxone binds to the same receptor as morphine and other opiates and so can be used as an antidote to excessive doses of opiates (antagonism). In other cases, such as when two organo phosphates are used together, both acting on acetylcholinesterase, the combined effect would be as expected (additive). 

The effects of heroin on the CNS are related to 6-monoacetylmorphine (6-MAM) and mainly morphine. The heroin crosses the blood-brain barrier due to the acetylic groups in position 3 and 6, that increase its lipophilicity. The morphinic compounds interact with the opioid receptors, mainly the p receptors, acting as an antagonist by mimicking the endorphin effects [9], Usually the first event occurs 30 s after its administration with a typical rush followed by a succession of euphoric sensations after a few minutes the user becomes calm, satisfied, and indifferent to his surroundings after 2-4 h typical restlessness accompanied with pain and an incessant demand for heroin sets in the craving. 

Morphine, the natural alkaloid from which almost all opiate analgesics have been evolved, is stereospecific in the receptor interactions that are responsible for its opioid actions, namely, analgesia, depression of respiration, dependence liability, and GIT disturbances. Compounds with natural (-) and unnatural (+) geometry may exhibit antitussive actions. 

In the original paper the proposition was made that the receptor of Fig. 13.4, formulated on the basis of the morphine molecule, was capable of accommodating other structural types of analgesic, and a common mode of drug-receptor interaction for both cyclic and acyclic analgesic molecules was implied. These aspects are now examined in the light of the more extensive evidence and data now available. 

The requirement for a phenol for opioid receptor interaction was recently revisited in a series of cyclazocine analogs in which the hydroxyl was replaced by a primary, secondary or tertiary amino group (399) and several of these analogs retained high affinity for opioid receptors the same modificationsto morphine decreased p-receptor affinity by at least 35-fold (400). 

A substantial reduction in analgesic potency was also observed for the m-hydroxyl derivative of the 2a-methyl reversed ester in which the preferred conformation of the phenyl ring is axial (444), suggesting that there can also be differences in receptor interactions for the axial aryl moiety in this derivative and in morphine. This in turn may be attributable to differences in the relative orientation of the aryl rings in the rigid morphine versus the phenylpiperidine derivatives in which the aryl ring is free to rotate. 

The major pharmacological actions of methadone, mediated by fi- and 6-receptor interactions, are similar to those of other opioids and include analgesia, sedation, respiratory depression, miosis, antitussive effects, and constipation. Methadone is administered as a racemic mixture (R,S- [ ] -methadone), but the analgesic activity is due almost entirely to the R(-)-isomer. When administered intramuscularly, methadone and morphine have equivalent analgesic potency. In contrast to morphine, methadone retains about 50% of its intramuscular analgesic potency when taken orally. ... 

The present knowledge on the subject is that there are at least four different receptors with which morphine can interact, three of which are analgesic receptors. The initial theory on receptor binding assumed a single receptor site, but this does not invalidate many of the proposals which were made. Therefore, it is informative to look at the first theory—the Beckett-Casy hypothesis. 

In addition to the endogenous opiate peptides, several other peptides function as neurotransmitters (e.g., substance P, vasoactive intestinal peptide). These agents are generally cleaved from larger peptide precursors. They can assume a variety of three dimensional shapes, making it difficult to assess the chemistry of peptide-receptor interactions. For this reason, no chemical agonists (other than morphine) or antagonists have been identified for peptide receptors. 

Recently, the endogenous morphine receptor ligand, enkephalin, has been iso= lated [305], identified chemically [306], and found to possess antinociceptive activity in mice after ICV injection [307], The interactions of the amines, enkephalin, and the cyclic nucleotides remain to be determined, and the scope for future studies of the mechanisms of action of the opiate analgesics becomes much wider as a result of these more recent studies. 

Receptor interactions morphine is a pure opioid agonist at mu, and is a weak agonist for kappa. 

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. 

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