Enkephalins and endorphins

Three endogenous opioids have been identified enkephalins, dynorphins and beta-endorphins. These opioid peptides selectively bind to the seven transmembrane GPCRs delta (8), kappa (k), and mu (p). Although dynorphin binds predominately to the k receptor, P-endorphines and enkephalins bind to p and 8 opioid receptors. It is important to note that the analgesia induced by opioids is mediated predominately throngh the p opioid receptor. In vitro studies have shown a decrease in the immnne function and proliferation following p-endorphin administration in rodents (Ray and Cohn 1999) and that the immunosuppressive effects by P-endorphins are steroid-independent (Berkenbosch et al. 1984 Nelson et al. 2000). 

The chemical transmitters may be small molecules— notably acetylcholine, norepinephrine, epinephrine, serotonin, dopamine, or histamine. Acetylcholine and norpeinephrine are the dominant neurotransmitters in the parasympathetic and sympathetic nervous systems, respectively. Dopamine and serotonin are employed primarily in the central nervous system. Neurotransmitters may also be more complex peptides (small proteins) such as substance P, vasopressin, endorphins, and enkephalins. The latter agents are of particular importance to our considerations of opium since they represent the endogenous opiates—agents that exist within the body whose actions are mimicked by exogenous, or outside, agents such as morphine, heroin, codeine, and so on. These neurotransmitters serve to convey information between neurons across the synaptic cleft (the junction where two neurons meet) or at the neuroeffector junction (the site between neuron and an innervated organ such as muscle or secretory gland). 

Opioid refers to any compound that acts like morphine, the most abundant alkaloid compound in opium. The term opioid includes substances that are derived from plants (such as morphine and codeine), those that occur naturally in the body (such as endorphins and enkephalins), and synthesized compounds (such as heroin and fentanyl). [Endorphins and enkephalins are discussed in Chapters 2 and 3. Fen-tanyi is discussed in Chapter 3.]... 

Codeine also activates pain-control circuits that descend from the section of the brain called the midbrain to the spinal cord, causing the release of naturally produced opioids called endorphins and enkephalins. The endorphins and enkaphalins bind to and activate receptors on cells in the spinal cord that prevent the transmission of pain signals. As discussed in Chapter 3, endorphins and enkephalins are your body s natural chemicals that allow you to feel no pain. ... 

So, there s actually a biological basis to the euphoric sensation associated with high-level physical activity, such as the runner s high described by long-distance runners and exercise gurus The euphoria is caused by the body s release of endorphins and enkephalins produced by prolonged exercise or stress on the body. 

Naloxone is an opiate antagonist which is used as an antidote to opiate overdoses. It has also been used in withdrawal programs, for babies born to addicted mothers, and in the study of the body s natural opiates, the endorphins and enkephalins. 

Production of a number of different hormones from the same precursor allows coordinate production of several hormones. Specific cleavage by the cell allows control of which peptides are produced (e.g., cleavage of prepro-opiocortin to corticotropin, /3-lipotropin, y-lipotropin, a-MSH, /3-MSH, y-MSH, endorphin, and enkephalin). 

Methadone, like all opiates, is a chemically simple compound that has a variety of effects on those who take it. But while other opiates exert powerful euphoric effects on a person by acting very much like chemicals called endorphins and enkephalins, methadone produces only a mild (or no) euphoria, to which patients quickly become tolerate. Endorphins and enkephalins are naturally produced inside the brain. When released in the brain s reward system, they produce a mind reward and users feel good as a result. Methadone and other opiates mimic these natural brain chemicals, which is why they are so addicting. 

The many rings of the morphine molecule include a benzene ring that fits into the receptors for the brain s own opiates (the endorphins and enkephalins). The nerve cells studded with these receptors recognize the morphine molecule by the close fit of the benzene ring and the binding of a critical nitrogen atom. Many other opioids duplicate these molecular features. 

Several of the small physiologically active peptides now are known to be derived from a single protein precursor synthesized by the pituitary gland (43). As shown in Figure 9, ACTH (adrenocorticotropic hormone), /3-LPH ( -lipotropic hormone), /3-MSH ( -melanocyte-stimulating hormone), /3-endorphin, and enkephalin result from the specific proteolytic cleavage of a precursor protein of approximately 8,000 daltons. 

Figure 9. The precursor protein giving rise to ACTH, /3-LPH, f3-MSH, /3-endorphin, and enkephalin through specific proteolysis (83)...

Examples of neuropeptides are endorphins and enkephalins, sometimes called naturally occurring opioid peptides because of their ability to bind to the same receptors as morphine. In this family of neuropeptides, there are at least 10 to 15 substances with purported actions on such diverse physiological systems as pain response, memory and learning, appetite, and temperature regulation. 

N4. Nice, E. C., and O Hare, M. J., Simultaneous separation of /3-lipoprotein, adrenocorticotropic hormone, endorphins and enkephalins by high performance liquid chromatography. J. Chromatogr. 162, 402-407 (1979). 

The endorphins and enkephalins bind to opiate receptors 1,K and 8 which are G protein linked. Opiate receptors are involved in the transmission of pain signals and the regulation of intestinal motility. Endorphins and enkephalins as well as morphine are pain killers that decrease the pain response in the CNS. Several other peptide neurotransmitters exist, but have been omitted in this review since interactions of alkaloids at their receptors is hardly known. 

Some neurotransmitters are closely related to proteins, differing from them only because they have relatively few residues. There are many known neurotransmitters endorphins and enkephalins are examples of peptides that carry out this role. 

Cleavage sites are shown in red in Figure 23.10. In the anterior pituitary, cleavage generates ACTH and / -lipotropin, and further processing in the central nervous system yields endorphin and enkephalin, among other products. 

Chronic cocaine abuse causes the brain to reduce its production of endorphins and enkephalins. The more severe the craving for cocaine, the greater number of C-11 car-fentanil binding receptors are seen in the frontal cortex, anterior cingulate cortex, caudate, and thalamus. To compensate for the drop in enkephalin production, the brain produces more opiate receptors to bind as much of the remaining enkephalin molecules as possible. This increase in the number of empty opiate receptors may be related to the feeling of craving for cocaine. 

Several amino-acids are important neurotransmitters in the c.n.s. Glutamic and aspartic acids seem to be excitatory transmitters in the entire brain. y-Aminobutyric acid (GABA) and glycine are important inhibitory transmitters, the former in supraspinal interneurons and the latter at spinal interneurons (Curtis and Johnston, 1970). Of the polypeptide neurotransmitters, the most studied have been the endorphins and enkephalins (see Section 12.8), Substance P (an undecapeptide that helps transmit the sense of pain (von Euler and Pernow, 1977, somatostatin, and gastrin, and cholecystokinin whose action in the gut has been well researched. For more on GABA, see Section 12.7. 

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