Opiate subtypes

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. 

Zukin, S.R. Differing stereospecificities distinguish opiate receptor subtypes. Life Sci 31 1307-1310, 1982. 

OPIATE RECEPTOR SUBTYPES AND BRAIN FUNCTION. Roger M. Brown, Ph.D. Doris H. Clouet, Ph.D. and David P. Friedman, Ph.D., eds. GPO Stock 017-024-01303-0 6... 

Clark JA, Liu L, Price M, Hersh B, Edelson M, Pasternak GW. Kappa opiate receptor multiplicity evidence for two U50,488-sensitive k3 subtypes and a novel k3 subtype. J Pharmacol Exp Ther 1989 251 461-468. 

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. 

The cloned opiate receptors expressed in homogeneous cell lines associate with guanine nucleotide binding (G) proteins which couple the receptors to cellular effector systems. G proteins consist of hetero-trimeric complexes of a, fj and y subunits [66]. Multiple subtypes of each subunit have been identified and cloned. In particular, three subtypes of Gi have been cloned that are approximately 90% identical in amino acid sequence. Furthermore, two splice forms of G0 have been identified. 

G.B. Stefano, W. Zhu, P. Cadet, T.V. Bilfinger, and K. Mantione, Morphine enhances nitric oxide release in the mammalian gastrointestinal tract via the mu 3 opiate receptor subtype a hormonal role for endogenous morphine. J. Physiol. Pharmacol. 55, 279-288 (2004). 

A 36-year-old male heroin addict is seen in the ED because he cannot be aroused from sleep On examination, he has shallow breathing and pinpoint pupils. Naloxone is administered, and the patient wakes up. Which of the opiate receptor subtypes that binds naloxone is responsible for reversing the respiratory depression and miosis ... 

Membrane-associated receptors are linked to transducing proteins (like G-proteins) in the inner portion of the membrane. G-protein coupled receptor (GPCR) families comprise a major class of the receptors that are pharmacologically relevant, such as muscarinic acetyl choline receptors, adrenoceptors, dopamine receptors, serotonine, opiate, peptide hormone, purinerg receptors, and also sensory chemoreceptors. A large variety of subtypes are described in the pharmacological literature. 

Several opiate receptors have been identified on cells of the nervous systems of animals and humans, with mu (p), kappa (k), and gamma (y) subtypes being predominant. These classical opiate receptors are G- protein coupled 7-transmembrane molecules.27 Opiates predominantly affect immune responses directly by ligation of p, k, and y opiate receptors, as well as non-classical opiate-like receptors, on immune cells and indirectly by binding to receptors on CNS cells. Studies conducted in vitro with opiate-treated immune cells demonstrated receptor-mediated reduced phagocytosis, chemotaxis and cytokine and chemokine production. These effects are linked to modulation of host resistance to bacterial, protozoan, viral and fungal infections using animal models, cell lines and primary cells. 

Kiefei JM, Cooper ML, Bodnar RJ. (1992b). Serotonin receptor subtype antagonists in the mediai ventrai meduiia inhibit mesencephaiic opiate anaigesia. Brain Res. 597 331-38. 

The chemical structures and biological activities of hundreds of opioid analgesics derived from the prototype opioid drug morphine are most comprehensively described in two books published in 1986, one entitled Opioid Analgesics, Chemistry and Receptors by Casy and Parfitt [1] and the other entitled Opiates by Lenz et al. [2]. Follow-up articles include those by Casy in 1989, entitled Opioid Receptors and their Ligands Recent Developments [3] which also includes sections on opioid peptides, affinity labelling and opioid receptor subtypes Rees and Hunter in 1990 [4] covering the... 

There are a host of receptors for each neurotransmitter with varying types of responses. For example, the four subtypes of adrenergic receptors which we saw in the PNS are also present in the CNS (ai, a2, Pl, P )-Cholinergic receptors come in two flavors, Mi and M2, while dopaminergic receptors show an elevation of cAMP levels upon stimulation of Di types and a decrease in cAMP after D2 stimulation. Opiate receptors (n,m, , k, ct) are the subject of intensive study as are 5-HT receptors. Drawn below are a few of the known CNS neurotransmitters and their activities as postulated. 

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. 

D-Ala-DELTORPHINS RECOGNIZE TWO DELTA OPIATE RECEPTOR SUBTYPES... 

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