Enkephalin opiate receptors

There are many peripheral organs that possess enkephalin opiate receptors the ileum, the most distal part of the small intestine, and the vas deferens are the most significant. The receptors in the ileum are responsible for the antidiarrheal activity of opiates. This is also the explanation for the severe constipation that may occur when people use opiates for pain relief. 

Opiates iateract with three principal classes of opioid GPCRs )J.-selective for the endorphiQS,5-selective for enkephalins, and K-selective for dynorphias (51). AU. three receptors have been cloned. Each inhibits adenylate cyclase, can activate potassium channels, and inhibit A/-type calcium channels. The classical opiates, morphine and its antagonists naloxone (144) and naltrexone (145), have moderate selectivity for the. -receptor. Pharmacological evidence suggests that there are two subtypes of the. -receptor and three subtypes each of the 5- and K-receptor. An s-opiate receptor may also exist. 

Simantov, R. Childers, D. and Snyder, S. The opiate receptor binding interactions of 3Hmethionine enkephalin, an opioid peptide. Fur J. Pharmacol 47 319-331, 1978. 

DiMaio J, Nguyen TM-D, Lemieux C, Schiller PW. Synthesis and pharmacological characterization in vitro of cyclic enkephalin analogs effect of conformational constraints on opiate receptor selectivity. J Med Chem 1982 25 1432-1438. 

The identification of the morphine receptor spurred an effort in many laboratories to find an endogenous agonist for which that receptor was normally intended. Ultimately, a pair of pentapeptides that bound quite tightly to opiate receptors were isolated from mammalian brains. These peptides, called enkephalins (2, 3), show many of the activities of synthetic opiates in isolated organ systems. They do in fact show analgesic activity when injected directly into the brain. It is thought that lack of activity by other routes of administration is due to their rapid inactivation by peptide cleaving enzymes. 

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. 

Neprilysin (enkephalinase, Endopeptidase-24.11, neutral endopeptidase, NEP, EC 3.4.24.11) bears considerable resemblance to other zinc-containing metallopeptidases it is an oligopeptidase that hydrolyzes enkephalins and a range of other active peptides. Enkephalins are endogenous ligands of opiate receptors, and the prolongation of their action via inhibition of enkephalinase... 

A clue to possible treatments for pain was discovered in the 1970s when scientists found specialized receptor cells in neurons called opiate receptors. These receptors appeared to he well suited for accepting natural painkillers that occur in the body, such as the enkephalins and endorphins. Enkephalins and endorphins are naturally occurring painkillers similar in their action to opium, morphine, and codeine. 

The enkephalins, derived from pro-enkephalin, are distributed much more widely in the CNS both in local circuit neurons and projection neurons, a distribution generally paralleling to that of the opiate receptors. Leu-enkephalin predominates over Met-enkephalin and both peptides are inhibitory. Enkephalin containing neurons are sparsely distributed in upper lay-... 

The plant alkaloids mimic the endogenous peptides enkephalins and endorphins (Chapter 12), which meditate nociception and sleep. There are three types of widely distributed opiate receptors. Mu receptors are concentrated in neocortex, striatum, thalamus, hippocampus, amygdala and spinal cord, delta receptors in neocortex and amydala, and kappa receptors in striatum, amygdala and hypothalamus (Mansour et al., 1988). 

Rigid Geometry Studies of Enkephalin The enkephalins are linear pentapeptides, H-Tyr-Gly-Gly-Phe-Met-NH2 (see Figure 2a.) and H-Tyr-Gly-Gly-Phe-Leu-NH2, which bind to several classes of opiate receptors in the mammalian brain including the same receptor as morphine(26,27). Enkephalins have drawn the interest of theoretical biophysicists for two reasons. First, because of their natural opiate activity, it is hoped that improved analgesics can be developed. Second, as pentapeptides, enkephalins are small enough that the molecule can be examined theoretically without excessive expense of computer time. 

There are three principal classes of opiate receptors, designated x, K, and 5, and there exist a number of drugs that are specific for each of these receptor types. However, most of the clinically used opiates are quite selective for the preceptor the endogenous opiates enkephalin, endorphin and dynorphin are selective for the p and 5, 5 and k receptors respectively. When activated by opioids these receptors produce biochemical signals that block neurotransmitter release from nerve terminals, a process that underlies their blockade of pain signaling pathways as well as other effects, such as constipation, diuresis, euphoria, and feeding. 

Naloxone will block the effects of opiate drugs and is used to treat overdoses. It was found that during trauma the use of naloxone would increase pain and prevent naturally induced analgesia. It was only a matter of time until the endogenous opiates, the endorphins (for endogenous morphine) and enkephalins, were discovered. Now there exists a whole nomenclature of opiate receptor types and their various effects. 

Pless, J., Bauer, W., Cardinaux, F., Closse, A., Hauser, D., Hugenin, R., Roemer, D., Buescher, H.-H., Hill, R.C. Synthesis, opiate receptor binding and analgesic activity of enkephalin analogues, Helv. Chim. Acta 1979, 62, 398-411. 

Bowen, W.K., Hellewell, S B., Keleman, M., Huey, R., Stewart, D. Affinity labelling of 6-opiate receptors using [D-Ala2, Leu5, Cys6]enkephalin covalent attachment via thiol-disulfide exchange, J. Biol. Chem. 1987, 262, 13434-13439. 

Opiates act on a variety of receptors. The three most important subtypes are the mu, delta, and kappa opiate receptors (Fig. 13—25). The brain makes its own endogenous opiate-like substances, sometimes referred to as the brain s own morphine. They are peptides derived from precursor proteins called pro-opiomelanocortin (POMC), proenkephalin, and prodynorphin. Parts of these precursor proteins are cleaved off to form endorphins or enkephalins, stored in opiate neurons, and presumably released during neurotransmission to mediate endogenous opiate-like actions (Fig. 13-25). However, the precise number and function of endogenous opiates and their receptors and their role in pain relief and other central nervous system (CNS) actions remain largely unknown. 

Finally, the discovery of a CNS receptor that is specific for benzodiazepines has led to some interesting speculation as to the possible existence of some type of endogenous sedative-like agent. The presence of a certain type of receptor to indicate that the body produces an appropriate agonist for that receptor makes sense. For instance, the discovery of opiate receptors initiated the search for endogenous opiate-like substances, which culminated in the discovery of the enkephalins. It has been surmised that certain endogenous steroids such as allopregnanolone (a metabolic byproduct of... 

The endorphins enkephalin and dynorphin possess natural analgesic (pain-relieving) qualities. When they bind to opiate receptors in the spinal cord, they suppress the ability of the brain to register pain. Heroin binds to these same opiate receptors in the brain and body. 

Chang KJ, Cuatrecasas P (1979) Multiple opiate receptors enkephalins and morphine bind to receptors of different specificity. J Biol Chem 254(8) 2610-2618... 

Snyder SH, Childers SR, Creese I. Molecular actions of opiates historical overview and new findings on opiate receptor interactions with enkephalins and guanyl nucleotides. Adv Biochem Psychopharmacol 1979 20 543-552. 

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