Beta-Endorphin

BEP neuronal cell bodies are primarily localized in the arcuate nuclei of the hypothalamus, and its terminals are distributed throughout the CNS, including the PVN of the hypothalamus (Kawano & Masuko, 2000).

From: Vitamins & Hormones , 2013

Telencephalon

David L. Felten MD, PhD , in Netter's Atlas of Neuroscience , 2022

13.36B Endogenous Opioid Systems: Beta-Endorphin, Dynorphins, and met-Enkephalin

Beta-endorphin neurons. Beta-endorphin neurons are found mainly in the arcuate nucleus in the hypothalamus (sometimes referred to as the peri-arcuate region) and, to a lesser extent, in the nucleus of the solitary tract (nucleus solitarius). Beta-endorphin neurons in the arcuate nucleus project axons to limbic structures, numerous hypothalamic regions, some thalamic sites, and numerous brainstem nuclei. Beta-endorphin neurons in nucleus solitarius project axons to the spinal cord. In the hypothalamus, beta-endorphin neurons innervate corticotropin-releasing hormone (CRH) neurons and inhibit CRH release. Beta-endorphin also inhibits activity of the stress axes. Beta-endorphin plays an important physiological role in analgesia, regulation and release of pituitary hormones, amelioration of anxiety, appetitive behavior, temperature regulation, and other visceral functions. Beta-endorphin binds to mu, kappa, and delta opioid receptors.

Dynorphin neurons. Dynorphins are found in neurons in the hippocampus (dentate gyrus mossy fibers), entorhinal cortex, other limbic structures (central amygdaloid nucleus, bed nucleus of the stria terminalis), basal forebrain (nucleus accumbens), striatum (caudate nucleus, putamen), brainstem nuclei, and the spinal cord. Dynorphins act mainly on kappa opioid receptors and generally inhibit excitatory neurons. Dynorphins play a functional role in pain responses, stress responses, appetitive behaviors, temperature regulation, learning and memory, and emotional control. Dynorphins also are involved in neurological disorders, including seizure disorders, addictive behaviors, and psychiatric disorders (depression, schizophrenia).

met-Enkephalin neurons. met-Enkephalin is found in small, local circuit neurons in widespread CNS sites, including the cerebral cortex, basal ganglia (medium spiny neurons), limbic sites (amygdala, hippocampal granule cells in the dentate gyrus, bed nucleus of the stria terminalis), basal forebrain (nucleus accumbens), thalamic and hypothalamic regions, many brainstem nuclei, and the spinal cord. met-Enkephalin cells also are found in the adrenal medulla and the anterior and posterior pituitary. met-Enkephalin acts mainly on delta opioid receptors and, to a lesser extent, on mu receptors. met-Enkephalin integrates sensory information related to pain perception and emotional responsiveness. met-Enkephalin also helps to modulate memory responses, some visceral hypothalamic responses (food and water regulation), and dopamine release in the mesolimbic and mesocortical pathways from neurons in the ventral tegmental area.

Endorphins and their Receptors

Catherine Abbadie , Gavril W. Abbadie , in Encyclopedia of the Human Brain, 2002

II.D.3 Pre-Opiomelanocortin

β-Endorphin has the most interesting precursor peptide, pre-opiomelanocortin (Fig. 2C). Unlike the other opioid precursor peptides, the β-endorphin precursor makes many important, biologically active peptides that are not related to the opioid family. The precursor for β-endorphin also generates ACTH, an important stress hormone, α-melanocyte-stimulating hormone (MSH), and β-MSH. The association of β-endorphin with stress hormones is intriguing in view of the many associations between stress and a diminished perception of pain. In the pituitary, stimuli that release ACTH also release β-endorphin.

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POMC Opioid Peptides

MARGARET E. SMITH , in Handbook of Biologically Active Peptides, 2006

Exercise and Stress

β-Endorphin is released from the pituitary into the blood during stress [33] and exercise [1]. It has been reported to mediate the euphoria experienced in pro longed exercise and to inhibit postexercise pain. Plasma β-endorphin has a number of actions on the periphery during exercise. β-Endorphin(1–31), β-endorphin(1–27), glycylglutamine, and the stabilized synthetic melanotrophin-potentiating factor (MPF) analog, N-acetyl-Lys-D-Lys-Sar-Glu, all increased the contractile response in isolated muscles of the rat [5]. β-Endorphin, glycylglutamine, and the MPF analog also reduced fatigue in isolated muscles stimulated at high frequency via the motor nerve. Furthermore, β-endorphin can be released by electrical stimulation of motoneurons [19], and POMC mRNA is upregulated in vivo in chronically stimulated motoneurons [12]. In addition β-endorphin, glycylglutamine, and the MPF analog stimulated glucose uptake in isolated skeletal muscles. β-Endorphin itself was more potent in increasing glucose uptake in contracting muscles than noncontracting muscles [5]. Its effect on glucose uptake was mediated partly via a ∂-opioid receptor [7]. Together these observations indicate an important role for β-endorphin in the insulin-independent uptake of glucose during exercise.

β-Endorphin is released from the pituitary into the blood under physical and emotional stress. Various nonopiate actions of human β-endorphin on the immune system have been reported. It binds to components of human complement and thymoma cells and stimulates the proliferation of lymphocytes. These actions may represent a modulation by β-endorphin of the immune system in stress situations. They were ascribed to the C-terminal tetrapeptide region of β-endorphin [35].

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POMC-Derived Opioid Peptides

Patricia J. McLaughlin , Ian S. Zagon , in Handbook of Biologically Active Peptides (Second Edition), 2013

β-Endorphin and Mu Receptor Functions

β-Endorphin serves as an agonist for mu opioid receptors and in vitro and in vivo studies have supported its function at these receptors to be neuroendocrine or neuroimmune in nature. Some studies suggest that β-endorphin has few central nervous system mediated effects when administered systemically because of the inherent difficulty for β-endorphin to cross the blood–brain barrier. Consequently, the classic effects of mu receptors including confirmation of analgesia and respiratory depression are not attributed to the endogenous peptide β-endorphin. 18 In vivo studies of the function of β-endorphin at mu opioid receptors suggest that prolactin release after systemic injections mediate many of the neuroendocrine responses. 1 Nonhuman primate studies in which β-endorphin is injected intravenously reported that this peptide most probably acts at mu receptors on the hypothalamus. However, the in vivo studies are not completely confirmatory as it is well known that β-endorphin is rapidly metabolized in the plasma and that other bioactive peptides may yield high affinity to opioid receptors and confer the function.

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Anterior Pituitary Hormones

Anthony W. Norman , Gerald Litwack , in Hormones, 1987

C Processing of β-Endorphin

β-Endorphin is produced as a cleavage product of β-lipotropin, as shown previously (see Fig. 5-16). A model of the proadrenocorticotropin/endorphin is shown in Fig. 5-13. It appears that β-endorphin (1–31) is first formed and this molecule is rapidly N-acetylated on its amino terminal residue and then converted more slowly to α-N-acetyl-β-endorphin (1–27) and subsequently to α-N-acetyl-β-endorphin (1–27). This posttranslational processing is summarized in Fig. 5-29.

Figure 5-29. Posttranslational processing of β-endorphin in rat intermediate pituitary.

 Reproduced from B. A. Eipper and R. E. Mains, J. Biol. Chem. 256, 5689–5695 (1981). Copyright © 1981

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Beta-Endorphin*

M. Lee , S.L. Wardlaw , in Encyclopedia of Stress (Second Edition), 2007

Structure, Synthesis, and Localization

β-Endorphin is a 31-amino-acid peptide that is derived from the larger molecular weight precursor protein proopiomelanocortin (POMC). β-Endorphin is one of the three major classes of endogenous opioid peptides. The other two classes are composed of the enkephalins and the dynorphins, which are derived from separate precursor proteins. POMC is synthesized independently in the anterior and intermediate lobes of the pituitary gland, in the brain, and in several peripheral tissues, including the gastrointestinal tract, reproductive tract, placenta, and cells of the immune system. The posttranslational processing of POMC is tissue specific and results in the production of peptides with very different biological activities. In the anterior pituitary, POMC is processed predominantly to adrenocorticotropin (ACTH) and β-lipotropin (β-LPH), but some β-endorphin is also produced. ACTH is secreted from the pituitary into the peripheral circulation and is critical for the maintenance of adrenocortical function and cortisol secretion. β-endorphin is also secreted in parallel with ACTH. In the brain, ACTH and β-LPH are further processed to yield α-melanocyte-stimulating hormone (α-MSH) and β-endorphin. The regulation of POMC processing is potentially important, as α-MSH has been shown to antagonize some of the effects of β-endorphin. The regulation of POMC gene expression and peptide release is also tissue specific, but under conditions of stress, β-endorphin is released from both the pituitary and the brain. The hypothalamic releasing factor corticotropin-releasing hormone (CRH), which plays a key role in coordinating the organism's response to stress, has been shown to stimulate pituitary and brain β-endorphin. β-endorphin exerts its effects by binding to specific opioid receptors, particularly the mu and delta receptors, which have been recently cloned and localized throughout the brain.

β-Endorphin is released from the anterior pituitary into the peripheral circulation in parallel with ACTH in response to a variety of stresses. Numerous studies have documented parallel increases in peripheral blood levels of ACTH and β-endorphin in response to exercise. This appears to be related to the intensity and duration of the exercise. A number of correlations between β-endorphin levels in blood and central nervous system or cardiovascular responses during stress have been reported. One must be cautious, however, in attributing a causal relationship for circulating β-endorphin, because in many instances, brain β-endorphin may also be stimulated at the same time. In addition, peripherally released β-endorphin does not readily cross the blood–brain barrier. In the brain, β-endorphin is synthesized in only two regions, the arcuate nucleus of the hypothalamus and the nucleus of the solitary tract in the brain stem, but β-endorphin fibers project widely to many regions throughout the brain.

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The Role of PKC Isozymes in Mediating Responses to Ethanol

JS Ellingson , in Comprehensive Handbook of Alcohol Related Pathology, 2005

The Role of PKC Isozymes in the EtOH-Modualted β-Endorphin Release

β -Endorphin, an opoid peptide made in the pituitary, brain, and other peripheral sites, is believed to be a neurotransmitter or neuromodulator, and appears to regulate some effects of EtOH intoxication. PKC isozymes affect the stimulated β-endorphin release from primary cultures of hypothalmic neurons by acute EtOH exposure and also the inhibited release resulting from chronic EtOH treatment (De et al., 2002). Acute treatment (3 h) with 50 mM EtOH stimulates the amount of PMA-induced release of immunoreactive β-endorphin, an effect reduced by chelerythrine chloride. Acute EtOH treatment increases the expression and translocation to the membrane fraction of only PKCδ and PKCɛ out of seven isozymes analyzed, whereas chronic EtOH treatment (24 h) decreases the expression and translocation of those two isozymes. The release of β-endorphin is modulated by P- and N-type calcium channels, and the EtOH upregulation of N-type channels is modulated by PKCɛ (see above) (McMahon et al., 2000). These findings raise the question whether the EtOH effects on neurosecretion of β-endorphin may occur in part by a PKCɛ-dependent modulation of N-type calcium channels.

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The Human Hypothalamus: Anterior Region

Bertalan Dudás István Merchenthaler , in Handbook of Clinical Neurology, 2021

β-endorphin-system

β-endorphin is a 31 amino acid peptide, deriving from processing of the precursor proopiomelanocortin (POMC) by prohormone convertases (Li et al., 1976). POMC processing also gives rise to other peptide hormones, including adrenocorticotropic hormone, as well α- and γ-melanocyte stimulating hormone. β-endorphin belongs to the endogenous opiates family, which also includes met-enkephalin, leu-enkephalin, and dynorphin. β-endorphin binds primarily to μ-receptors with high affinity but also binds to δ- and κ-receptors with lower affinity. β-endorphin provides analgesia and a feeling of well-being. As an important neurotransmitter/neuromodulator, it also regulates multiple functions in the brain and periphery (Simantov and Snyder, 1976).

β-endorphin-IR neurons are fusiform in shape with two processes emanating from the opposite poles of the cells (Fig. 4.11A ), but a few multipolar cells located in the infundibular nucleus (Fig. 4.11B) are also present. The β-endorphin-IR neurons are located in a single, well-defined cell cluster in the infundibulum/median eminence of the human diencephalon (Sukhov et al., 1995) (Fig. 4.12), where axons are often found in close proximity to portal vessels (Dudas and Merchenthaler, 2004, 2006) (Fig. 4.11C), and often form juxtapositions with β-endorphin-IR perikarya. These potential connections with portal vessels have not been seen in rodents in retrograde labeling experiments (Merchenthaler et al., 1989; Merchenthaler, 1990) suggesting species differences in endorphin functions. A similar pattern of POMC expression has been previously reported by Sukhov et al. (1995) in the human hypothalamus (Korf and Moller, 2021).

Fig. 4.11

Fig. 4.11. β-endorphin-immunoreactive (IR) elements in the human hypothalamus. (A) Fusiform and (B) multipolar β-endorphin-IR neurons contact β-endorphin-IR axon varicosities (arrowheads) in the infundibulum. (C) β-endorphin-IR fibers are in close proximity of portal vessels in the median eminence. The lumen of the vessel is denoted by asterisk. Scale bar: 10   μm (A, B); 40   μm (C).

 Reprinted with permission from Elsevier. Dudas B, Merchenthaler I (2004). Topography and associations of β-endorphin and luteinizing hormone-releasing hormone neuronal systems in the human diencephalon. Neuroscience 124: 221–229.

Fig. 4.12

Fig. 4.12. Stereoscopic images of the human hypothalamus reconstituted from 30-μm-thick sections, illustrating the distribution of beta-endorphin-immunoreactive (IR) perikarya (dots). Stereoscopic images can be seen using U or parallel vision as described for Fig. 4.2. Abbreviations: AC, anterior commissure; Inf, infundibulum; MB, mamillary body; and OCh, optic chiasm.

β-endorphin-IR fibers are in the periventricular zone of the hypothalamus, where they form a loose network of immunoreactive axon varicosities. Such axons can also be observed along the diagonal band of Broca, at the basal part of the lamina terminalis cinerea and around the anterior commissure. At the medial preoptic region, most of the β-endorphin-IR fibers are located periventricularly, but immunoreactive axons can also be seen in the dorsomedial subdivision of the ventromedial nucleus. A delicate β-endorphin-IR fiber network is associated with the portal vessels in the infundibulum/median eminence (Fig. 4.11C), projecting laterally from the infundibulum at the base of the diencephalon. The lateral hypothalamic zone contains only few fibers. In the posterior hypothalamus, scattered β-endorphin-IR axons populate the area around the mamillary bodies and the tuberomamillary nucleus.

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Hypothalamic Changes Relevant to Reproduction in Aging Male Rodents

David A. Gruenewald , Alvin M. Matsumoto , in Functional Neurobiology of Aging, 2001

C. β-Endorphin

β-Endorphin is an endogenous opioid peptide that is thought to exert a tonic inhibitory influence upon GnRH secretion and to be an important regulator of reproductive function (Cicero et al., 1979; Delitala et al., 1983). β-Endorphin is derived from a larger precursor peptide, proopiomelanocortin (POMC), and is produced by neurons located in the arcuate nucleus, many of which synapse onto GnRH neurons in the MPOA.

Administration of the opiate antagonist naloxone in male Sprague–Dawley rats was found to induce a marked increase in serum LH levels in young animals, which was attenuated with aging (Steger et al., 1980b). However, more recently, in vitro studies in males of the same rat strain found that less naloxone was needed to induce GnRH release from hypothalami of older compared to young adult rats (Nazian et al., 1998). The reasons for this apparent discrepancy are unclear. Hypothalamic β-endorphin content decreases with age in various rat strains such as Wistar (Dax et al., 1988), Sprague–Dawley (Gambert et al., 1980; Barden et al., 1981; Forman et al., 1981), and Long–Evans (Dorsa et al., 1984) rats, which could represent either a decrease in β-endorphin production, or an increase in β-endorphin release or metabolism. Alterations in posttranslational processing of hypothalamic POMC occur in aging male F344 rats, with increased amounts of acetylated β-endorphin peptides and shorter forms of β-endorphin (βE1–27 and βE1–26) (Wilkinson and Dorsa, 1986; Dax et al., 1988). β-endorphin is thought to be an endogenous ligand for μ-opioid receptors, which are thought to be involved in the regulation of LH secretion (Panerai et al., 1985), and the number of hypothalamic μ-opioid receptors was found to decrease with aging in male Sprague–Dawley rats (Piva et al., 1987). However, the effects of decreased hypothalamic β-endorphin content, altered posttranslational processing of β-endorphin and reduced μ-receptor binding with aging on opiate tone and GnRH and gonadotropin secretion are unclear.

We tested the hypothesis that the age-related decrease in GnRH secretion in male rats is due to increased β-endorphin synthesis, by comparing prepro-POMC (ppPOMC) mRNA levels in the arcuate nucleus of intact young (3-month-old), middle-aged (11-month-old), and old (23-month-old) male F344 rats. ppPOMC mRNA levels were quantified by in situ hybridization histochemistry. We found a significant decrease in both cellular ppPOMC mRNA content and in the number of labeled POMC neurons in old compared to younger rats.

These findings in male F344 rats suggest that β-endorphin synthetic capacity is decreased with aging. However, as for the effects of aging on GnRH, these observations in aging male F344 rats are potentially confounded by elevated progesterone levels. To our knowledge, no studies of aging effects on POMC gene expression in the arcuate nucleus or other aspects of β-endorphin regulation of reproductive axis aging have been performed in aging male Brown Norway rats, but our results in the F344 model suggest that the decline in GnRH secretion in old male rats is not a result of increased β-endorphin synthesis.

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Gastrointestinal Hormones

L. Terenius , T. Hokfelt , in Advances in Metabolic Disorders, 1988

C β-Endorphin-Immunoreactive Neurons

β-Endorphin-immunoreactive fibers are found in low numbers in the gastrointestinal tract, much lower than those positive for enkephalin (Schultzberg et al., 1980). β-Endorphin fibers are mainly seen in the circular muscle layer and in the myenteric plexus at most levels of the gastrointestinal tract of both rat and guinea pig. Leander et al. (1984) apparently recorded somewhat larger numbers of nerve fibers in the same layers but also discovered some nerve cell bodies in the myenteric plexus. More recently Wolter (1984, 1985, 1986) has analyzed β-endorphin-LI in the intestine both at the light and electron microscopic level. Thus, there is agreement that there may be some small populations of neurons expressing products of the proopiomelanocortin precursor.

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