Α-ENDORPHIN

β-END is derived from the C-terminal region of the common precursor POMC. It is composed of 31 aa residues in mammals. The N-terminal 5 aa sequence, Tyr-Gly-Gly-Phe-Met, is identical to Metenkephalin, which is derived from proenkephalin, and is essential for analgesic activity. Acetylation occurs at the N-terminal tyrosine in a substantial amount of β-END in the pars intermedia. Nonacetylated β-END is the active form, and acetylated β-END is the inactive form. α-END and γ-END correspond to β-END(1–16) and β-END(1–17), respectively. In the frog Xenopus laevis, N-acetyl-β-END(1–8) has been shown to be the terminal product of β-END processing. The N-terminal 5 aa sequence sometimes undergoes mutation in species having two or more pomc genes. In the barfin flounder, in which three POMC sequences have been reported, Tyr-Gly-Gly-Phe-Met is changed to Ser-Gly-Arg-Phe-Met. In lampreys, one of the two POMCs (arbitrarily termed proopiomelanocortin, POM), which is synthesized in the pars intermedia, could be a source of Met-enkephalin. The Met-enkephalin sequence is segregated with basic amino acids from the rest of the β-END sequence consisting of the 28-aa identification of β-END(8–35), suggesting the liberation of the Met-enkephalin sequence.

β-END and a related peptide such as β-END(1–27) are agonists for the μ-opioid receptor (MOR), although these peptides also bind to the δ-opioid receptor with slightly weaker affinities. MOR is a subtype of opioid receptor belonging to the GPCR superfamily. The location of MOR in human chromosomes is 6q24–q25.

DAMGO, sufentanil, hydromorphone, fentanyl, and nalbuphine are agonists. Naloxone, naltrexone, nalmefene, alvimopan, and levallorphan are antagonists.

β-END exhibits opiate-like analgesic activity that is 18–33 times more potent than that of morphine, and its actions are blocked by the specific opiate antagonist naloxone hydrochloride. It also affects feeding, sexual behavior, and learning, and modulates neuroendocrine function when administered into the cerebral ventricle or the brain. In peripheral tissues, β-END is associated with the cardiovascular and immune systems, although the significance of peripherally circulating β-END remains to be fully elucidated. N-Acetylated forms of β-END do not bind to opioid receptors. MOR, DOR, and KOR are expressed in goldfish interrenal cells, where β-END suppresses the basal release of cortisol and inhibits the cortisol-releasing activity of ACTH. N-Acetylated forms of β-END have no effect on cortisol release. In mammals, the effects of β-END on coticosteroidogenesis are inconsistent, depending on the dose, the functional state of the adrenocortical cells, and the properties of animals used for investigations. In amphibians, β-END inhibits corticosteroid secretion from interrenal tissue. Additionally, β-END is associated with food intake and the immune system in fish.

Endorphin is an endogenous morphine secreted from the pituitary. Sources are corticotropes in the pars distalis and melanotropes in the pars intermedia. The fact that END is derived from a precursor protein called proopiomelanocortin (POMC) was demonstrated in 1979 using the pars intermedia in the bovine pituitary.

There is a correlation between endogenous opioid peptides, especially β-END, and alcohol abuse. The consumption of alcohol activates the endogenous opioid system. The consumption of alcohol results in an increase in β-END levels in the brain regions that are associated with reward. However, it has also been observed that habitual alcohol consumption leads to β-END deficiency. People with a genetic deficit in β-END are particularly susceptible to alcoholism. The plasma levels of β-END in subjects genetically at high risk of excessive alcohol consumption show lower basal activity of β-END. Recently, β-END has been shown to play a role in the pathophysiology of major depressive disorder in addition to a variety of physiological functions such as cardiovascular regulation and several kinds of behavior and stress responses.