Prodynorphin-derived peptides

III. Nociceptive Behavior Induced by i.t.-Administered Prodynorphin-Derived Peptides and Polycationic Compounds... 

Principal Nonopioid Effects of Prodynorphin-Derived Peptides... 

Kuzmin, A., Madjid, N., Terenius, L., Ogren, S. O., and Bakalkin, G. (2006). Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolyticlike and locomotor behavior in mice. Neuropychopharmacology 31, 1928-1937. 

Dynorphins (Dyn), opioid peptides released from the precursor protein prepro-dynorphin, (prepro-enkephalin B). Dynorphin A (Dyn A), YGGFLRRIRP KLKWDNQ, dynorphin B (Dyn B), YG GFLRRDFK WT, a-neoendorphin (— neoendorphins), prodynorphin-derived... 

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. 

Note Three distinct families of peptides have been identified the enkephalins, the endorphins, and the dynorphins. Each family is derived from a distinct precursor polypeptide and has a characteristic anatomical distribution. These precursors are now designated as proenkephalin (also proenkephalin A), proopiomelanocortin (POMP), and prodynorphin (also proenkephalin). 

The endogenous opioid peptides have a range of affinities for the different types of opioid receptor. Some met-enkephalin derivatives, for example, show affinity for mu and delta receptors, whereas other peptides, derived from proenkephalin, show a preference for the delta sites. All peptides from prodynorphin act predominantly on kappa sites, while beta-endorphin behaves like the enkephalins and shows selectivity for the mu and delta sites. 

Prodynorphin contains three copies of Leu-enkephalin with carboxy-termi-nus extended polypeptides of various lengths known as dynorphin A (or dynorphin 1-17), dynorphin B (dynorphin 1-13), or a- and 3-neoendorphin. These peptides derived from prodynorphin are selective to kappa receptors and can also be further broken down to Leu-enkephalin. The identification of the delta receptor (or the enkephalin receptor) was a direct consequence of the discovery of enkephalins. This chapter will review the major events that are important for the identification of delta receptors and the subsequent cloning of delta receptor genes, and eventually all other opioid receptor genes. 

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. 

ENDORPHINS. Each of these families derives from different precursors, proenkephalin, prodynorphin, and PROOPIOMELANOCORTIN, respectively. There are also at least three classes of OPIOID RECEPTORS, but the peptide families do not map to the receptors in a simple way. 

Dynorphinhas not been nearly as well studied as other smaller opioid peptides. Although several peptides with high affinity for k receptors are obtained from prodynorphin (see Section 3.4 above), SAR studies have focused on derivatives of dynorphin A (see Refs. 656, 753 for reviews). Dynorphin A is a heptadecapep-tide, but dynorphin A-(l-13) accounts for essentially all of the activity of the larger peptide (754). Further truncation of dynorphin A-(l-13) from the C-terminus identified the basic residues Arg and Lys as important for k receptor potency and selectivity (263). Thus, typically, dynorphin A-(l-13) or A-(l-l 1) has been used as the parent peptide for further modification. 

In addition to P-endorphin, P-LPH contains the amino acid sequence of another endogenous opioid, met-enkephalin. However, this peptide is not the product of P-LPH breakdown, but rather arises from a precursor molecule loiown as pro-enkephalin. Pro-enkephalin is widely distributed in neurons throughout the brain and spinal cord. Some pro-enkephalin is found in the pituitary gland, but most is localized in the catecholamine-synthesizing cells of the adrenal medulla and is co-released with epinephrine and norepinephrine. In the medulla, pro-enkephalin gives rise to met-enkephalin (Tyr-Gle-Gle-Phe-Met) and leu-enkephalin (Tyr-Gle-Gle-Phe-Leu) and to larger opioid peptides. A third family of endogenous opioid peptides is derived from prodynorphin, a prohormone stored primarily in the poste-... 

At least 15 endogenous peptides have now been discovered, varying in length from 5 to 33 amino acids (the enkephalins and the endorphins). These compounds are thought to be neurotransmitters or neurohormones in the brain and operate as the body s natural painkillers as well as having a number of other roles. They are derived from three inactive precursor proteins—proenkephalin, prodynorphin, or proopiomelanocortin (Fig. 12.38). 

Opium, derived from poppies, relieves pain and induces euphoria by binding to "opiate receptors" in the brain. These opioid drugs mimic the actions of three peptide families in the brain known as the endorphins, the enkephalins, and the dynorphins. These peptides, along with several nonopioid peptides (MSH, ACTH, lipotropin) are cleaved from the protein precursors pro-opiomelanocortin (POMC), proenkephalin, and prodynorphin (Fig. 3.5). 

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