Opioid system dynorphins

The body modulates pain through several processes. The endogenous opiate system consists of neurotransmitters (e.g., enkephalins, dynorphins, and /1-endorphins) and receptors (e.g., fl, S, k) that are found throughout the CNS. Endogenous opioids bind to opioid receptors and modulate the transmission of pain impulses. 

The classic endogenous opioid peptides are derived from one of three families of precursors proopiomelanocortin (POMC), pro-dynorphin, and pro-enkephalin. Many active opioid peptides are derived from these three, but the best known are )S-endorphin, enkephalin, and dynorphin. POMC is produced by nuclei in the hypothalamus and medulla (Khachaturian et al. 1985 Watson et al. 1978 Bloom et al. 1978). Enkephalin and dynorphin neurons are distributed to all levels of the central nervous system (Hokfelt et al. 1977 Khachaturian et al. 1983 Sar et al. 1978 Khachaturian et al. 1985). 

In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A—through its binding to (kappa) opioid receptors—remains controversial. Dynorphin A is also found in the dorsal horn of the spinal cord, where it may play a critical role in the sensitization of nociceptive neurotransmission. Increased levels of dynorphin can be found in the dorsal horn after tissue injury and inflammation. This elevated dynorphin level is proposed to increase pain and induce a state of long-lasting hyperalgesia. The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system but dependent on the activation of the bradykinin receptor. Moreover, dynorphin A can bind and activate the N -methyl-D-aspartate (NMDA) receptor complex, a site of action that is the focus of intense therapeutic development. 

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. 

Mattheakis et al., 1994). A library of 1012 DNA molecules was used with E. coli ribosome display utilizing a coupled in vitro transcription-translation system. This library was selected for binding to the monoclonal antibody D32.39, which originally bound dynorphin B, a 13-residue opioid peptide, with 0.29 nM affinity. Five cycles of ribosome display resulted in several different peptides with affinities to the antibody ranging from 7.2 to 140 nM affinity. Yet, a peptide with a sequence similar to dynorphin B was not isolated. 

Subsequently, numerous peptides with opioid-like effects have been found in the central nervous system and in peripheral tissues. These endogenous opioid peptides vary in size, but their amino terminals mostly share a similar enkephalin sequence of amino acids. Currently, four separate, individually gene-derived families of endogenous opioid peptides are recognized the endorphins, the enkephalins, the dynorphins and the endomorphins [17a], -Endorphin interacts predominantly with n and 6 receptors, Leu-enkephalin and Met-enkephalin interact predominantly with 5 receptors, dynorphin shows preference for k receptors [17b], while endomorphins 1 and 2 exhibit... 

Gao L, Yu LC (2004) Involvement of opioid receptors in the oxytodn-induced antinociception in the central nervous system of rats. Regul Pept 120 53-58 Garden LR, Ibrahim M, Wang R, Wang Z, Ossipov MH, Malan TP Jr, Porreca F, Lai J (2004) Mouse strains that lack spinal dynorphin upregulation after peripheral nerve injury do not develop neuropathic pain. Neurosdence 123 43-52 Garraway SM, Anderson AJ, MendeU LM (2005) BDNF-induced fadlitation of afferent-evoked responses in lamina II neurons is reduced tifter neonattil spinal cord contusion injury. J Neurophysiol 94 1798-1804... 

LaGraize SC, Borzan J, Peng YB, Fuchs PN (2006) Selective regulation of pain affect following activation of the opioid anterior cingulate cortex system. Exp Neurol 197 22-30 Lai J, Luo MC, Chen Q, Porreca F (2008) Pronociceptive actions of dynorphin via bradykinin receptors. Neurosci Lett 437 175-179... 

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