8 Opioid receptors sites

Classification of the narcotic analgesics is based on their activity at the opioid receptor sites. Although five categories of opioid receptors have been identified, only three of these receptors affect the action of the narcotic... 

Partial agonists and antagonists compete with agonists for opioid receptor sites and exhibit mixed agonist-antagonist activity. They may have selectivity for analgesic receptor sites and cause fewer side effects. 

Where are the major opioid receptor sites located ... 

These heterocyclic opioid agents, with a diverse structure, act by binding to one or more of the opioid receptor sites which are to be found on neural (and some other sites) in the central and peripheral nervous systems. It is now recognized that these are the natural receptor sites for recognition of the endogenous members of the peptide opioid neurotransmitters families, which are found in neuronal tissue of the brain and elsewhere. 

Some opioids, including the benzomorphans (e.g. cyclazocine and pentazocine), bind appreciably to a further site, the (sigma) o-receptors that, unlike the opioid receptors detailed, have psychotomimetic potential, and patients may experience hallucinations. The a-site is best not classed as an opioid receptor site, in as much as it is not blocked by normal opioid receptor antagonists, such as naloxone - a fact of clinical Importance. On the other hand, it is now clear that the ORL, receptors are not sensitive to naloxone, though receptor activation can sometimes cause analgesia. 

Prior to cloning of the opioid receptors, affinity for these receptors was most commonly determined by the use of homogenates or membrane fractions from rat, guinea pig, or mouse brain, which contain all three types of opioid receptors. The relative amounts of different opioid receptor types vary between species, however, particularly for k receptors. In rat brain k opioid receptors constitute only about 10-15% of the total number of opioid receptor sites (124), whereas in species such as guinea pig they represent approximately 30% of the total opioid receptor population (125). Over 80% of the opioid receptors in the guinea pig cerebellum are k receptors (126), so this tissue was frequently used in K-receptor bind-... 

The opioids probably do not play an important role in the regulation of neuroendocrine function because blockade of opioid receptor sites has either minor or no effect on the basal or stimulated release of most pituitary hormones. However, there is evidence that central opioids may toni-cally inhibit the rate of hypothalamic GnRH release after puberty in males. 

The initial report of the potent biological activity of 112 generated a great deal of interest. Epibatidine was found to be 200 times and 500 times more potent than morphine in causing hot plate analgesia and in eliciting a Straub-tail reaction, respectively. It had a very low affinity for opioid receptor sites, which suggested an alternate mechansim of action was involved [322]. 

Portoghese PS, Larson DL, Sayre LM, et ai. A novei opioid receptor site directed aikyiating agent with irreversibie narcotic antagonistic and reversibie agonistic activities. J Med Chem 1980 23 233-234. 

Methadone works in the same way as naltrexone, binding to opioid receptor sites. Unlike other narcotics, it does not produce stupor. However, methadone does prevent the physical symptoms associated with withdrawal. 

It has been proposed that the drug binds to its opioid receptor site in the form of the less stable ring-flip conformer containing an axial amino substituent. Indeed, strategic introduction of an adjacent cis- (but not trans Make models ) methyl group (which prefers the equatorial position) places the nitrogen axial, causing a dramatic increase in activity. 

The opioid peptides vary in their binding affinities for the multiple opioid receptor types. Leu- and Met-enkephalin have a higher affinity for 5-receptors than for the other opioid receptor types (68), whereas the dynorphin peptides have a higher affinity for K-sites (69). P-Endorphin binds with equal affinity to both p- and 5-receptors, but binds with lower affinity to K-sites (70). The existence of a P-endorphin-selective receptor, the S-receptor, has been postulated whether this site is actually a separate P-endorphin-selective receptor or is a subtype of a classical opioid receptor is a matter of controversy (71,72). The existence of opioid receptor subtypes in general is quite controversial although there is some evidence for subtypes of p- (73), 5-(74), and K-receptors (72,75), confirmation of which may be obtained by future molecular cloning studies. 

Fig. 5. Schematic diagram of the presumed arrangement of the amino acid sequence for the 5-opioid receptor, showing seven putative transmembrane segments three intracellular loops, A three extracellular loops, B the extracellular N-terrninus and the intracellular C-terrninus, where (0) represents amino acid residues common to ] -, 5-, and K-receptors ( ), amino acid residues common to all three opioid receptors and other neuropeptide receptors and (O), other amino acids. Branches on the N-terruinal region indicate possible glycosylation sites, whereas P symbols in the C-terminal region indicate...

The pharmacological and/or adverse effects of a drug can be reversed by co-administration of drugs which compete for the same receptor. For example, an opioid receptor antagonist naloxone is used to reverse the effects of opiates. Drugs acting at the same site with opposite effects also can affect each other, e.g. the reduction in the anticoagulant effect of warfarin by vitamin K. 

Administration of naloxone prevents or reverses the effects of the opiates. The exact mechanism of action is not fully understood, but it is believed that naloxone reverses opioid effects by competing for opiate receptor sites (see Chap. 19). If the individual has taken or received an opiate, the effects of the opiate are reversed. 

Carr DJJ, DeCosta BR, Kim C-H, Jacobson AE, Bost KL, Rice KC, Blalock JE (1990) Antiopioid receptor antibody recognition of a binding site on brain and leukocyte opioid receptors. Neuroendocrinology 51 552-560... 

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