Ho

Naloxone

Morphine

FIGURE 5-31 Structures of the opiate receptor antagonist, naloxone, and the opiate receptor agonist, morphine.

binding site. A summary of the properties of opioid receptors is presented in Table 5-4.

Some general remarks can be made about opioid receptors. /¿-Receptors may mediate most opioid analgesic effects, although some negative effects are listed in Table 5-4. /c-Receptors produce analgesia at the spinal level and do not contribute to (drug) dependence. S-Receptors are important to the periphery but may also contribute to analgesia. Figure 5-33 shows the interactions of opiate peptides in the pain pathway.

Administration of the synthetic glucocorticoid, dexa-methasone, inhibited the secretion of both ACTH and /3-endorphin. The glucocorticoid functions by reducing the level of translatable mRNA encoding both ACTH and endorphin. Processing of the precursor RNA is unaffected. The exact molecular mechanism by which glucocorticoid receptor operates negatively on the POMC gene is still under study. The receptor may act through negative hormonal response elements in the proopiomelanocortin promoter.

B. /3-Endorphin Receptor

Interaction of /3-endorphin with receptor involves predominantly the ¿¿-opioid receptor. Enkephalins, morphine, and naloxone, a specific inhibitor of analgesic action (see Figure 5-31), were not as potent competitors as /3-endorphin for endorphin-specific binding sites. Interestingly, small amounts of morphine and codeine are produced by the brain. Enkephalins predominantly bind to the 5-opioid receptor, and dynor-phins predominantly bind to the K-receptor. From the point of view of the /3-endorphin molecule, there are three binding sites, two of which could explain binding to distinct receptors. Binding to the S-receptor is located in the Met-enkephalin segment, as shown in Figure 5-32. The /¿-receptor, specific for the morphine-binding site, is in the carboxy terminus (Figure 5-32). The middle segment of /3-endorphin is the antibody-

C. Processing of /3-Endorphin

/3-Endorphin is produced as a cleavage product of /3-lipotropin, as shown previously (see Figure 5-10). It appears that /3-endorphin (1-31) is the first formed, and this molecule is rapidly N-acetylated on its amino-terminal residue and then converted more slowly to

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