Prodynorphin

Dynorphin may also influence nociception at the spinal level. The levels of prodynorphin mRNA and immunoreactive dynorphin increase in the chronic inflammatory arthritic model (158). Dynorphin also inhibits morphine or P-endorphin-induced analgesia in naive animals and enhances analgesia in tolerant animals, indicating that this peptide may have a regulatory role in opioid analgesia (159). This effect does not appear to be mediated by a classical opioid receptor, since des-tyrosine dynorphin, which does not bind to opioid receptors, also antagonizes morphine analgesia (160). 

Mansour A, Fox C, Meng F, Akil H, Watson S. Kappa 1 receptor mRNA in the rat CNS comparison of kappa receptor binding and prodynorphin mRNA. Mol Cell Neurosci 1994 5 124-144. 

The number of neural genes known to contain CREs is growing as more and more genes are cloned. Prominent examples are tyrosine hydroxylase, c-fos, proenkephalin, prodynorphin, somatostatin and vasoactive intestinal polypeptide (VIP). Expression of these genes has been... 

Endogenous opioids are peptides that are cleaved from the precursors proenkephalin, pro-opiomelanocortin, and prodynorphin. All contain the amino acid sequence of the pentapeptides [Met]- or [Leuj-enkephalin (A). The effects of the opioids can be abolished by antagonists (e.g., naloxone A), with the exception of buprenorphine. 

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. 

Cenci, M. A., Lee, C. S. and Bjorklund, A. (1998). L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin-and glutamic acid decarboxylase mRNA. Eur. J. Neurosci. 10(8), 2694-2706. 

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

Principal Nonopioid Effects of Prodynorphin-Derived Peptides... 

A consensus of different studies appears to be that the spinal dynorphin system plays an inhibitory role in nociceptive transmission mediated through the K-opioid receptor in an acute pain state, and a facilitative role mediated through an NMDA receptor mechanism in a chronic pain state when the K-opioid receptor became tolerant due to sustained activation by endogenous dynorphins (Xu et al., 2004). Our studies suggest that the prodynorphin system also has a pronociceptive function in normal uninjured animals. 

Dores, R. M., and Akil, H. (1987). Spedes-spedfic processing of prodynorphin in the posterior... 

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. 

Ji, R. R., Befort, K., Brenner, G.J., and Woolf, C.J. (2002). ERK MAP kinase activation in superficial spinal cord neurons induced prodynorphine and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J. Neurosci. 22, 478—485. 

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