P-Endorphins

In the anterior pituitary gland (see Hormones, anteriorpituitaryhormones), both adrenocorticotropic hormones (ACTH) and the endogenous opiate hormone, P-endorphin, are synthesized from a common prohormone (2) (see Opioids,endogenous). In the adrenal medulla, five to seven copies of another opiate hormone, methionine—enkephalin (Met-enkephalin), and one copy of leucine—enkephalin (Leu-enkephalin) are synthesized from each precursor molecule (3). 

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. 

At the time of the discovery of Met-enkephalin, its sequence was observed to be identical to that of residues 61—65 contained in the C-fragment of the pituitary hormone p-Hpotropin [12584-99-5] (p-LPH) (see Hormones), first isolated in 1964 (11). In 1976, the isolation of a larger peptide fragment, P-endorphin [60617-12-1] that also displayed opiate-like activity was reported (12). This peptide s 31-amino-acid sequence comprised residues 61—91 of P-LPH. Subsequentiy, another potent opioid peptide, dynorphin [72957-38-17, was isolated from pituitary (13). The first five amino acids (qv) of this 17-amino-acid peptide are identical to the Leu-enkephalin sequence (see Table 1). 

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. 

Dynorphin may also influence nociception at the spinal level. The levels of prodynorphin mRNA and immunoreactive dynorphin increase in the chronic inflammatory arthritic model (158). Dynorphin also inhibits morphine or P-endorphin-induced analgesia in naive animals and enhances analgesia in tolerant animals, indicating that this peptide may have a regulatory role in opioid analgesia (159). This effect does not appear to be mediated by a classical opioid receptor, since des-tyrosine dynorphin, which does not bind to opioid receptors, also antagonizes morphine analgesia (160). 

Litde is known about metaboHc inactivation of ( -endorphin and the dynorphins. NEP, and to a lesser extent APN, are only weaMy active against P-endorphin (183). Enzymes are known which degrade P-endorphin in vitro under nonphysiological conditions (202) or which inactivate P-endorphin by N-acetjlation (203). Alack of specific degradative enzymes for these peptides may account for their relatively long half-life in vivo though this has not been definitively estabUshed. 

P-endorphin [60617-12-1] H-TyrGlyGlyPheMetThrSerGluLysSerGlnThrProLeu-ValThrLeuPheLysAsnAlalle V alLys Asn AlaHisLys LysGlyGln- OH... 

Three endogenous opioids have been identified enkephalins, dynorphins and beta-endorphins. These opioid peptides selectively bind to the seven transmembrane GPCRs delta (8), kappa (k), and mu (p). Although dynorphin binds predominately to the k receptor, P-endorphines and enkephalins bind to p and 8 opioid receptors. It is important to note that the analgesia induced by opioids is mediated predominately throngh the p opioid receptor. In vitro studies have shown a decrease in the immnne function and proliferation following p-endorphin administration in rodents (Ray and Cohn 1999) and that the immunosuppressive effects by P-endorphins are steroid-independent (Berkenbosch et al. 1984 Nelson et al. 2000). 

Labov J.B. Katz Y., Wysocki C.J., Beauchamp G., et al. (1988). Levels of immunoreactive P-endorphin in rostral and caudal sections of olfactory bulbs from male guinea pigs exposed to odors of conspecific females. Ann NY Acad Sci 510, 432-435. 

Fragments of the peptide hormone p-lipotropin have been found to show similar binding to opiate receptors. These molecules, the endorphins, show profound CNS activity in experimental animals. It is of interest that one of these, p-endorphin, incorporates in its chain the exact sequence of amino acids that constitutes methionine enkaphalin. 

Opioid peptide A neuropeptide (e.g., p-endorphin), whose actions are mimicked by opiate drugs. 

FIGURE 1 8-5 Tissue-specific processing of the pro-opiomelanocortin (POMC) precursor yields a wide array of bioactive peptide products. Processing of the POMC precursor varies in various tissues. In anterior pituitary, adrenocorticotropic hormone (ACTH (1-39)) and P-1 ipo tropin (P-LPH) are the primary products of post-translational processing. Arcuate neurons produce the potent opiate P-endorphin (P-endo (1-31)) as well as ACTIK1 -13) NIT,. Intermediate pituitary produces a-melanocyte-stimulating hormone (aMSH), acetylated P endof 1 31) and P-endo(l-27). NTS, nucleus tractus solitarius. 

Yeager, M.P. et al., Effect of morphine and P-endorphin on human Fc receptor-dependent and natural killer cell functions, Clin. Immunol. Immunopathol., 62, 336, 1992. 

E Atherton, M Caviezel, H Fox, D Harkiss, H Over, RC Sheppard. Peptide synthesis. Part 3. Comparative solid-phase synthesis of human P-endorphin on polyamide supports using t-butoxycarbonyl and fluorenylmethoxycarbonyl. 

Naloxone precipitates nicotine withdrawal in mice Naloxone induces place aversion in nicotine-dependent rats Naloxone prevents nicotine alleviation of nic. withdrawal Mu and delta agonists reduced mec-precipitated aversion Kappa antagonist suppresses mec.-precipitated aversion P-Endorphin metabolite Gly-Glu blocks aversiveness of mec-precipitated withdrawal Mec precipitates hyperalgesia in nicotine-tolerant rats NAcc Met-enkephalin increased Striatum preproenkephalin mRNA increased... 

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