Endorphins, discovery

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). 

Since the discovery of the enkephalins in 1975 [11] a large number of endogenous opioid peptides have been detected in mammals, and at present three distinct families of opioid peptides are known (for a review, See Ref. 12). These are the enkephalins, the endorphins (a-, (J-, and y-), and the dynorphins and neoendorphins. The recently discovered endomor-phins [13] also may represent endogenous opioid peptides. Peptides with opioid activity have also been isolated from tryptic digests of milk casein... 

Endorphins likely came first, and then humans made the discovery of how opium contains compounds that mimic the effect of endorphins. Thus, opioids have endorphin activity. Why this is so is something you should be sure to discuss with your instructor. 

Endogenous opioid peptides. Extensive processing is also involved in formation of analgesic opioid peptides, which are present naturally in the brain (see also Section B). Tire formation of (1-endorphin in the hypothalamus from prepro-opiomelanocortin (Fig. 30-2) has already been mentioned. Prior to the discovery of P-endorphin, the pentapeptides Met-enkephalin and Leu-enkephalin (Table 30-4) were discovered and were found to compete with opiate drugs for receptors in the brain. Tire larger P-endorphin, which contains the Met-enkephalin sequence at its N terminus, is a far more potent opiate antagonist than are the enkephalins. Since the Met-enkephalin sequence within P-endorphin is not flanked by basic residues, it apparently is normally not released. Two other recently discovered brain peptides are endomorphin-1 (YPWF-NH2) and endomorphin-2 (YPFF-NH2). They are also potent agonists for the opioid receptors, especially the p receptor (see Section B,10).,61a,61b... 

The demonstration of the existence of strictly defined SARs. which is perhaps Ihe most important criterion of drug action at a specific receptor site, has made possible the most important pharmacologic discoveries. For example, the analgesic actions of morphine and related agents, which are indicative of specific receptors, led to die discovery of endogenous opiate peptides, i.e., the leucine and methionine enkephalins and endorphins. 

Some naturally occurring neurotransmitters may be similar to drugs we use. For example, it is well known that the brain makes its own morphine (i.e., beta endorphin), and its own marijuana (i.e., anandamide). The brain may even make its own antidepressants, it own anxiolytics, and its own hallucinogens. Drugs often mimic the brain s natural neurotransmitters. Often, drugs are discovered prior to the natural neurotransmitter. Thus, we knew about morphine before the discovery of beta-endorphin marijuana before the discovery of cannabinoid receptors and anandamide the benzodiazepines diazepam (Valium) and alprazolam (Xanax) before the discovery of benzodiazepine receptors and the antidepressants amitriptyline (Elavil) and fluoxetine (Prozac) before the discovery of the serotonin transporter site. This un-... 

The opium alkaloids codeine and morphine served as models for the synthesis of naloxone, an important analog used to treat and diagnose opiate addicts, and also led to the discovery of endogenous opioids (enkephalins and endorphins) (see Chapter 47). Similarly, A9-tetrahydro-cannabinol (THC), the component of Cannabis sativa responsible for the central nervous system (CNS) effect, has also been found to reduce nausea associated with cancer chemotherapy (see Chapter 18). 

Subsequent conversion into heroin 2 was first reported in 1874 by Wright in the UK as a result of boiling morphine acetate the process was commercialised by Bayer AG in 1898. The subsequent use and abuse of these compounds is much too complex to discuss here, but one major discovery came in the early 1970s when Pert and Synder reported the identification of opioid receptors in brain tissue.17 This report was followed closely by the identification of endogenous morphine-like substances in 1975 by Kosterlitz and Hughes,18 which over the next few years led to the identification of enkephalins, endorphins and dynorphins—all of which had the common N-terminal sequence of Tyr-Gly-Gly-Phe-(Met/Leu), leading to the concept that morphine actually mimics this sequence.19... 

Since the discovery and characterization of P-endorphin (31 amino acids) as an opioid peptide in 1976, the opinion has been widely held that this peptide has a role in the control of pain (Akil et al., 1984 Basbaum and Fields, 1984 Loh et al 1976 Rossier et al., 1977). POMC-derived P-endorphin is considered to be a key component of the endogenous antinociceptive system attenuating the stress- and inflammation-induced hyperalgesia (Rossier et al., 1977 Stein et al., 1990 Sun et al., 2003). It binds with high affinity to both MOR and DOR (Akil et al., 1984). Pain stimulation induces PAG release of 3-endorphin and the ICV administration of 3-endorphin produces analgesia (Akil et al., 1984). Similarly, both spinal and peripheral administration of 3-endorphin evokes antinociceptive effects in different pain models (Chung et al., 1994 Stein et al., 1990 Suh et al., 1994 Suh et al.,... 

The discovery of endorphins also raises interesting questions. Why have the human brain and the poppy evolved chemicals with similar effects when they are so unlike each other Is this fact a mere coincidence or does it suggest a deep relationship between people and plants that underlies the age-old inclination to experiment with vegetable drugs And what does it say about the "nat-... 

Endogenous opioid peptides (endorphins, dynor-phins, enkephalins), have been termed the brain s own morphine. Their discovery in 1972 explained why the brain has opioid receptors when there were no opioids in the body. These peptides attach to specific opioid receptors, mainly p (mu), 5 (delta) or K (kappa) located at several spinal and multiple supraspinal sites in the CNS. Opioid receptors are part of the family of G-protein-coupled receptors (see p. 91) and act to open potassium channels and prevent the opening of voltage-gated calcium channels which reduces neuronal excitability and inhibits the release of pain neurotransmitters, including substance P. 

Some of the endorphins, dynorphin and enkephalins are about as active as morphine and some have higher efficacy. The discovery of the function of natural opioid mechanisms in physiology and pathology opens up possibilities for major developments in pain management, and indeed, wider, for endogenous opioid mechanisms may play a role, e.g. in shock. 

Heroin was first synthesized from morphine over a century ago. Since then, it has become one of the most abused substances. Research into why it produces such powerful effects has led to the discovery of specific opiate receptors and endogenous opioids (enkephalins and endorphins). These peptides appear to be neurotransmitters involved with the sensation of pain and pleasure. A number of opiates and synthetic opioids are available and can lead to dependency, including morphine, heroin, propoxyphene (Darvon), methadone, meperidine (Demerol), pentazocine (Talwin), hy-dromorphone (Dilaudid), oxycodone (Percodan), and hydrocodone (Vicodin, Damason-P), and codeine. 

Distribution, Metabolism, and Excretion Mechanisms of Opiate Action Discovery of Endorphins What Do Endorphins Do ... 

One of the most exciting developments in the neurosciences was the discovery in the 1970s of the neural mechanisms of action of opiate drugs. Research on this topic led to the discovery of a class of brain chemicals called the endorphins, which apparently ftinction as ncurotransmitters. It is now believed that heroin, morphine, and other opiate drugs produce their effects by triggering activity in the brain s endorphin systems (Meyer Quenzer, 2005 Goldstein, 2001). We will review the events that led to these discoveries and consider how these developments have helped us understand the effects of opiate drugs. 

During the mid-1970s the search for endogenous ligands for opioid receptors led to the discovery of peptides with opiate-like activity. The first opioid peptides reported were the pentapeptides leucine and methionine enkephalin (Sand 4) (7), followed shortly thereafter by dynorphin A (3 8) (260,261) and ( endorphin (51)(262). Because these peptides are structurally distinct from the alkaloid opiates, the term opioid was introduced to describe all compounds, both nonpeptide and peptide, with opiate-like activity. These mammalian opioid peptides share a common N-terminal tetrapeptide sequence, but differ in their C-terminal residues (Fig. 7.9). They also differ in... 

The search for this natural analgesic took many years, but ultimately led to the discovery of the enkephalins and the endorphins. The term enkephalin is derived from the Greek, meaning in the head , and that is exactly where the enkephalins are produced. The first enkephalins to be discovered were the pentapeptides Met-enkephalin and Leu-enkephalin. 

---