Beta-endorphin-(1-27) is a naturally occurring antagonist to etorphine-induced analgesia.

Abstract

The potent opioid peptide ,-endorphin is found in the brain and pituitary with two related fragments, fi-endorphin-(1-27) and f3-endorphin-(1-26 Recent studies have shown that P-endorphin (p-EP) is found in the pituitaries and the brain of various species together with two related peptides: P-EP-(1-27) and its des-His27 or des-Tyr27 derivative ,-EP-(1-26). Each of these peptides occurs also in an a-N-acetyl form (1-5). Studies of the regional distribution and biosynthetic pathways of the 1-EPrelated peptides in the brain and pituitaries have shown distinctive proportions of these forms in specialized areas arising from differential proteolytic cleavages and acetylation of ,3-EP (6-8). Of various peptides related to P-EP, only the unmodified hormone possesses potent analgesic properties. The formation of its derivatives is accompanied by loss of analgesic activity (9-12).Since no particular role had been reported for these truncated and/or acetylated peptides, it was suggested that post-translational inactivation of,-EP might be an important all-or-none metabolic process maintaining a physiological level of bioactive endorphin in the brain (5, 6). However, the diversity and natural abundance of these inert opioid peptides, in regard to such a simple switch mechanism for inactivation, have given the impetus to search for more specific biological functions. We have recently reported on the inhibition of the analgesic activity of ,-EP by B-EP-(1-27) (13). This particular fragment retains 30% of the binding potency of the parent hormone for brain opioid receptors and <2% of its analgesic potency. It diminishes the analgesic effect of j-EP when coinjected intracerebroventricularly (icv) into mice in doses that are compatible with those found in the brain. To provide further evidence in support of the hypothesis that natural fragments of 8-EP might be implicated in the control of pain perception, we have studied effects of B-EP-(1-27) and 3-EP-(1-26) on the modulation of antinociception induced both by j3-EP and by the highly potent opiate agonist etorphine in mice. Effect of icv administered opiates or peptides on heat escape latency was assessed by the tail-flick method (18), using groups of 10 mice (male Swiss Webster, 20-25 g; Simonsen Laboratories, Gilroy, CA) per dose. Percentage analgesia was calculated as described (19). Median antinociceptive dose (AD50), 95% confidence limits and slope of the logarithm of the dose vs. probit (% analgesia) curves were calculated by a nonlinear least-squares regression to a 2 parameters logistic. AD50 values were calculated for each peptide or opiate alone and in combination with various fixed doses of putative antagonist. The ratio of the AD50 value in the presence of antagonist to that in its absence (dose ratio, x) was then calculated for each dose of antagonist (13,20). MATERIALS AND METHODSCompetitive antagonism was quantified by use of the apparent pA2 (the negative logarithm of the antagonist dose required to reduce the effect of a dose of agonist by one-half) fo...

Processing of Thyrotropin-Releasing Hormone (TRH) Prohormone in the Rat Olfactory Bulb Generates Novel TRH-Related Peptides*

“…It has been repeatedly demonstrated that differential processing mechanisms exist for activation of plurifunctional biosynthetic precursors in various tissues (22)(23)(24)(25)(26)(27)(28). The tissue-specific sets of end products resulting from alternate processing are usually released in a coordinate manner and could exert distinct or coordinated biological activities (28)(29)(30)(31).…”

Endomorphin‐Stimulated [35S]GTPγS Binding in Rat Brain: Evidence for Partial Agonist Activity at μ‐Opioid Receptors

“…For example, the endogenous cannabinoid receptor ligand anandamide is a partial agonist in rat brain (Mackie et al, 1993;Childers et aI., 1994). Moreover, it has been reported that the opioid peptide ß-endorphin 1_27 may act as an agonist (McKnight et al, 1983), an antagonist (Hammonds et al, 1984;Nicholas and Li, 1985;Suh et al, 1987;Bals-Kubik et al, 1988), or a lowefficacy partial agonist at ‚u-and 8-opioid receptors (Hong et al, 1993) in various experimental paradigms. This is unlike ß-endorphin1.31, which has been found to act as a full agonist at ‚u receptors, and a full-or high-efficacy partial agonist at 6-opioid receptors (Law et al, 1983;Selley and Bidlack, 1992).…”

POMC: The Physiological Power of Hormone Processing

“…223). As described above, ␤-LPH is cleaved by PC2 to give ␥-LPH and ␤-endorphin which can be further cleaved by CPE to ␤-endorphin (1-27) and ␤-endorphin (1-26), which have much less analgesic activity (269). These enzymes act in secretory granules within cells, so this implies that the cleavage of ␤-endorphin to the COOH-terminally truncated ␤-endorphin peptides is a mechanism to reduce opioid activity in tissues where other POMC peptides are released for non-opioid functions.…”

“…If it is the latter, then there may be processing mechanisms to inactivate ␤-endorphin when melanocortins are activated, and vice versa. Although inactivation by acetylation of ␤-endorphin is not thought to occur in the hypothalamus (258), it may be that processing to ␤-endorphin (1-27) and ␤-endorphin (1-26) is a mechanism that at least reduces its activity (269). As early as the 1920s there were suggestions that the endogenous opioid system was involved in the regulation of food intake and body weight, with morphine causing a decrease in body weight but a "voracious" appetite.…”