Enkephalins brain sites

McLawhon, R.W. West, R.E., Jr. Miller, R.J. and Dawson, G. Distinct high-aff1nity binding sites for benzomorphan drugs and enkephalin in a neuroblastoma-brain hybrid cell line. Proc Natl MM USA, 78 4309-4313, 1981. 

If opiates are such addictive and potentially lethal compounds, why does the body respond to them As with the cannabinoids (Chapter 7), it has been discovered that the body and brain possess numerous opiate-specific receptor sites. As many as nine receptor subtypes have been identified, with three of them being the most important p (mu), k (kappa) and 8 (delta). The finding that the distribution of opiate receptors did not parallel the distribution of any known neurotransmitter prompted the search for and identification of a number of endogenous compounds specific to these receptors. These enkephalins and endorphins are manufactured within the brain and other body systems (especially the gut and intestines) and form the body s natural response to pain. They appear to be produced in bulk chains of amino acids called polypeptides , with each active neurotransmitter being composed of around five amino acid molecules. These active neurotransmitters are subsequently cleaved from the larger polypeptides at times of demand for example, it has been demonstrated that the plasma levels of these active compounds rise during childbirth, traumatic incidents and vigorous physical exercise. 

ORLi receptors. Although nociceptin is selective for ORLi receptors, the other three peptides show a marked degree of promiscuity with regard to the classical opioid receptors (p, 8, and k). Endorphins occur in the brain (almost exclusively in neurones which have their somata in the infundibular nucleus) and in the adenohypophysis. Enkephalins are found on many sites in the CNS but also occur in the adrenal medulla and in the gut wall. Dynorphins are also found in the CNS and in the gut (for review, see Gutstein and Akil 2006). 

The chloromethyl ketone of [D-Ala2,Leu5]enkephalin (DALECK) [66, 67] showed moderate preference for p receptors over 3 receptors in rat brain and was used for covalent labelling of opioid receptors [67, 68], Somewhat higher p selectivity was displayed by the tetrapeptide derivative H-Tyr-D-Ala-Gly-MePhe-CH2Cl (DAMK), which labelled irreversibly and selectively high-affinity p binding sites [69],... 

Related peptides with terminal Phe reduced to phenylalaninol (Pheol) or replaced by N-phenethylamide also show potencies of the morphine order in the GPI assay. The derivative Tyr-D-Met(0)-Gly-N-methylphenethylamide, termed syndyphalin, is about as potent as morphine in mice after sc injection by MTF and WR tests with selectivity for p,-sites.<76 77,194) A Reckitt and Colman group(78) has described some similar derivatives 8 based on the protected tetrapeptide Tyr-D-Ala-Gly-MePhe the GPI and MVD potencies reveal their potent -receptor activities. The compound terminated by a reduced Gly residue (DAGO) is in fact one of the most selective p,-ligands available (see p. 356). All three peptides 8 were much more stable to brain and plasma enzymes than Leu-enkephalin, and two had activities close to or better than that of morphine in a rat in vivo test. 

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. 

Candace Pert, together with Solomon Snyder (Johns Hopkins, Baltimore, USA), first identified opioid receptors in the brain in 1972 (Eignre 1.5). In 1975 Hans Kosterlitz and John Hnghes (Aberdeen, UK) reported the existence of an endogenons morphine-like snbstance and named it enkephalin (for in the head ). Enkephalins, endorphins, and dynorphins bind to specific receptor sites in the brain. 

Enkephalins—Pentapeptide endorphins, found in many parts of the brain, that bind to specific receptor sites, some of which may be pain-related opiate receptors. 

Since P-endorphin is located within the hypothalamus and the pituitary, and has a relatively longer duration of action, it tends to be viewed as a neurohormone. Enkephalins, on the other hand, are more extensively distributed, are very rapidly degraded, and are primarily located in synaptosomal areas. The additional observation that enkephalin release following depolarization of brain (and intestinal) tissues is calcium dependent makes it more realistic to categorize them as neurotransmitters or modulators of synaptic function. Binding sites (receptors) for opioids are found, particularly in synaptosomal brain fractions. The enkephalins are located in neurons whose distribution correlates well with that of the receptors. In fact, regional distribution of peptides and their receptors are closely parallel, as would be predicted for a neurotransmitter system. 

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