Endogenous Opioid Neuropeptides

The endogenous ligands for the opioid receptors are peptides known as the endorphins (endogenous morphine) or opio-peptins. These include the pentapep tides methionine-enkephalin and leucine-enkephalin and a hep tapep tide and octapeptide version of methionine-enkephalin, all derived from preproenkephalin p-endorphin derived from proopiomelanocortin a-and p-dynorphin derived from prodynorphin endomorphin-1 and -2, whose precursor has not been definitively identified and orphanin FQ or nociceptin, derived from OFQ/N precursor protein. These peptides are discussed in more detail in Chapter 34. 

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There are three families of endogenous opioid neuropeptides that interact with opioid receptors enkephalins, endorphins and d)morphins (Carvey 1998). These neuropeptides have varying affinities for the three types of opioid receptors, though none binds exclusively to only one receptor type (Meunier et al 1995). Beta-endorphin shows equal activity at x and 8 opioid receptors with lesser affinity for k receptors. Met-enkephalin and leu-enkephalin have high affinity for 8 receptors, their affinity for p, receptors is one-tenth of that for 8 receptors and they have negligible affinity for k receptors. Dynorphdns A and B have high affinity for K receptors but also bind to x and 8 receptors (Corbett et al 1993). 

The dorsal horn of the spinal cord contains many transmitters and receptors. Some of these include peptides, eg. substance P, somatostatin and neuropeptide Y excitatory amino acids, e.g. glutamate and aspartate inhibitory amino acids, e.g. y-aminobutyric acid (GABA) nitric oxide endogenous opioids adenosine and the monoamines, e.g. serotonin and noradrenaline. There is, therefore, diverse therapeutic potential for... 

For a growing number of neurotransmitters, direct neurotrophic actions have been reported (for a review see Schwartz, 1992 Schwartz and Tani-waki, 1994). These transmitters are serotonin, acetylcholine, norepinephrine, glutamate and endogenous opioid peptides. Some of these neurotrophic transmitters may also be produced by astrocytes. The family of neurotransmitters synthesized by astrocytes comprises y-aminobutyric acid, glutamate, proenkephalin, neuropeptide Y, somatostatin and others. Martin (1992) has coined the term gliotransmitter for such substances. The role of gliotransmission in development and function of the mature nervous system has not been firmly established yet. It can be anticipated, however, that neurotrophic activity of astroglia-derived transmit-... 

There are dozens of presynaptic receptors for endogenous peptides. This review will focus on receptors for four peptides or peptide families the opioid peptides, neuropeptide Y and related peptides, adrenocorticotropic hormone (corticotropin, ACTH), and the orexins. This choice is representative, since part of the receptors inhibit and part of them facilitate transmitter release moreover, the receptors under consideration are coupled to the major G proteins, namely Gl/(), Gs and Gq (Table 1). 

Figure 3 Cysteine protease and subtilisin-like protease pathways for proneuropeptide processing. Distinct cysteine protease and subtilisin-like protease pathways have been demonstrated for pro-neuropeptide processing. Recent studies have identified secretory vesicle cathepsin L as an important processing enzyme for the production of the endogenous enkephalin opioid peptide. Preference of cathepsin L to cleave at the NH2-terminal side of dibasic residue processing sites yields peptide intermediates with NH2-terminal residues, which are removed by Arg/Lys aminopeptidase. The well-established subtilisin-like protease pathway involves several prohormone convertases (PC). PC1/3 and PC2 have been characterized as neuroendocrine processing proteases. The PC enzymes preferentially cleave at the COOH-terminal side of dibasic processing sites, which results in peptide intermediates with basic residue extensions at their COOH-termini that are removed by carboxypeptidase E/H.

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