User:Vrwclemson/Endorphins/Bibliography

Reference 1: 75 years of opioid research: the exciting but vain quest for the Holy Grail: Opioids and opioid peptides

 * John Hughes and Hans Kosterlitz were the first to identify endogenous ligands, enkephalins for their opioid activity in pig brain extract.
 * [beta]-endorphin was identified for containing the [Met]-enkephalin sequence and further demonstrated opioid agonist activity.
 * (Corbett) Opioid peptides are classified into families based on their precursor. [beta]-endorphin was identified as being a cleavage product of pro-opiomelanocortin.  [beta]-endorphin binds [mu]- and [delta]-receptors with much greater affinity than with [kappa]-opioid receptors.
 * Opioid receptors are g-protein coupled receptors have the ability to inhibit neurotransmitter release in both the PNS and CNS.
 * [Mu]-receptors in animals mediates euphoria, [kappa]-receptors mediate dysphoria, and [Mu]-receptors mediating supraspinal analgesia.
 * This came after the discovery of a receptor that was proposed to produce analgesic effects of morphine and other opioids.

Reference 2: Neuroscience: Purves, Dale, 6th ed.

 * [beta]-endorphins are involved in mediating stress.
 * Pre-proopiomelanocortin is a pre-propeptide produced in the rough endoplasmic reticulum and converted into proopiomelanocortin with the removal of an N-terminus signal sequence signaling the molecule to be delivered to the Golgi. After exocytosis from the Golgi, proteolytic enzymes and other modifications including glycosylation, phosphorylation, and disulfide bond formation cleaves the propeptide into active ACTH and [beta]-lipotropin. [beta]-lipotropin is cleaved into [gamma]-lipotropin and [beta]-endorphin.
 * The discovery of opioid peptides in the 1970s was during the search for endorphins (analgesic endogenous compounds) in drug addiction research.
 * They mimicked morphine, from opium poppy, and were separated into categories based on their pre-propeptide: endorphins from pr-proopiomelanocortin, enkephalins from pre-proenkephalin A, and dynorphins from pre-dynorphin.
 * Opioid receptors are G-protein-coupled.
 * [mu]-. [delta]-, and [kappa]-opoid receptors are implicated in addiction pathways within the brain.
 * Opiate drugs (analgesics) tend to have the greatest affinity for the [mu]-opioid receptor
 * Amino acid sequences of endogenous opioid peptides
 * [alpha]-endorphin: Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr
 * [alpha]-neoendorphin: Try-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys
 * [beta]-endorphin: Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Val-Lys-Asn-Ala-His-Lys-Gly-Gln
 * [gamma]-endorphin: Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu
 * Endorphins can be found in the same region that pain modulation takes place, the periaqueductal gray matter.

Reference 3: Opioid Receptors

 * Endogenous opioid ligands have an N-terminus opioid motif of Tyr-Gly-Gly-Phe with either Met or Leu.
 * [beta]-endorphin binds systemic [mu]- and [delta] receptors and is considered an anti-nociceptive agent.
 * Released by leukocytes to inhibit nociceptors and thus produce analgesia, reducing the sensation of pain.
 * Opioid receptors functions:
 * [mu]-receptors: “respiratory depression, sedation, reward/euphoria, nausea, urinary retention, biliary spasm, & constipation.”
 * [delta]-receptors: “reward, respiratory depression, convulsions.”

Reference 4: The effects of [beta]-endorphin: state change modification

 * [beta]-endorphins act in two ways at the same time: axonal transport in neurons to the designated area and local volume transmission. One acts immediately while the other has more long-term effects within the Central Nervous System.
 * Regionally and globally, long-term effects produced by [beta]-endorphin are done through cerebral spinal fluid.
 * [beta]-endorphin neurons are predominately located in the arcuate nucleus (ARH) of the hypothalamus and produce the propeptide proopiomelanocortin.
 * Moderate release of [beta]-endorphin was found in 1982 to produce a state of well-being, while increased concentrations cause analgesia and euphoria.
 * [beta]-endorphins are involved in the following behaviors: regulation of food in-take, reward and meditation, and pain control mechanisms.

Reference 5: 60 years of POMC: Lipotropin and [beta]-endorphin: a perspective

 * 1976, [beta]-endorphin found to cause analgesia and have greater potency than morphine in rats.
 * Isolated [beta]-endorphins from camel pituitary glands.
 * [beta]-endorphins are found to produce longer lasting effects and was hypothesized to be because its protein conformation is not as vulnerable to attack by proteolytic enzymes.

Reference 6: Action of proteolytic enzymes on lipotropins and endorphins: Biosynthesis, biotransformation and fate

 * [beta]-endorphin can be inactivated by the enzyme acetyltransferase, which transfers an acetyl group to the N-terminus of [beta]-endorphin.
 * The hypothalamus pro-opiomelanocortin nuclei rely on proteolytic processing to create [beta]-endorphin and not acetyltransferase.
 * In 1976, [alpha]- and [gamma]-endorphin sequences were isolated and identified from ovine hypothalamic-hypophyseal extracts.
 * [alpha]- and [gamma]-endorphins result from proteolytic cleavage of [beta]-endorphin between the Thr(16)-Leu(17)-Phe(18) residues in the pituitary gland.
 * [beta]-endorphins are synthesized from pro-opiomelanocortin in the pituitary gland and in the brain.
 * [beta]-endorphins are less susceptible to degradation as its most stable conformation protects its N- and C- termini from exopeptidases.

Reference 7: Subcellular pathways of [beta]-endorphin synthesis, processing, and release from immunocytes in inflammatory pain

 * The pituitary gland is the primary site for POMC synthesis.
 * POMC polypeptide enters ER as directed by signal sequence.
 * Processing begins at trans-Golgi network
 * Binds to membrane-bound carboxypeptidase E, a sorting receptor.
 * Pro-peptide convertase, PC1, cleaves POMC into ACTH and [beta]-lipotropin
 * Pro-peptide convertase, PC2 cleaves [beta]-lipotropin into [beta]-endorphin and [beta]-MSH

Reference 8: Mechanism of sorting proopiomelaocortin and preoenkephalin to regulated secretory pathway of neuroendocrine cells

 * In the trans-Golgi network, POMC binds membrane-bound carboxypeptidase E, which buds off into granules.

Reference 9: Post-translational modifications of proopiomelanocortin in vertebrates and their biological significance

 * The pituitary gland is the major site of POMC synthesis and processing.
 * Adult human pituitary glands generally contain PC1, thus, majority of the final products are POMC cleavage into ACTH and [beta]-LPH.
 * Other mammalian cells have PC2 capable of cleaving [beta]-LPH to generate [beta]-endorphin at the C-terminus.

Reference 10: The C-fragment of lipotropin – a potent analgesic

 * Wilhelm Feldberg and Derek George Smyth in 1977 found β-endorphin to be much stronger than morphine, yet is still from opiate receptors by naloxone, an identified morphine antagonist.

Reference 11: Endorphins and Schizophrenia

 * Post-cleavage, [beta]-endorphin is stored in vesicles to be delivered to the synaptic terminal. During vesicle maturation, [beta]-endorphins can be cleaved into [alpha]- and [gamma]-endorphins.
 * Acetylated [beta]-endorphins are more stable and less susceptible to degradation by endoproteases.
 * [alpha]-endorphin denoted as [beta]-E-(1-16) and [gamma]-endorphin denoted as [beta]-E-(1-17)
 * [alpha]-endorphin and [gamma]-endorphin are primarily found in the anterior and intermediate pituitary.
 * While [beta]-endorphin is studied for its opioid activity, [alpha]-endorphin and [gamma]-endorphin lack affinity for opiate receptors and thus do not effect the body in the same way that [beta]-endorphin does. Some studies have characterized [alpha]-endorphin as similar to psychostimulants and [gamma]-endorphins to neuroleptics separately.

Reference 12: POMC-Derived Opioid Peptides

 * The term “endorphins” at the time was assigned to any peptide that demonstrated morphine-like activity.
 * There are many modified forms of [beta]-endorphin, and some have little to no activity.
 * Proteases PC2 and PC1 facilitate cleavage of ACTH and [beta]-LPH.
 * The analgesic effects [beta]-endorphin produces when binding to opioid receptors is greater reduced without its C-terminus.
 * [beta]-endorphin has been found to bind with the greatest affinity to mu-opioid receptors (MORI). But can still bind other opioid receptors, which determine the effect of the ligand.