Opioid system enkephalins

In addition to the weU-defined opioid systems in the central nervous system, the three opioid peptides and their precursor mRNA have also been identified in peripheral tissues. ( -Endorphin is most abundant in the pituitary, where it exists in corticotroph cells with ACTH in the anterior lobe and in melanotroph cells with MSH in the intermediate lobe (59). Enkephalin and pre-pro-enkephalin mRNA have been identified in the adrenal medulla (60) and this has been the source of material for many studies of pro-enkephalin synthesis and regulation. Pre-pro-enkephalin mRNA has also been identified in the anterior and posterior lobes of the pituitary (61). mRNA for all three opioid precursors has been identified in the reproductive system (62—64). POMC... 

In contrast, blockade of delta2 opioid receptor by naltriben reduced RB 101 induced antinociceptive response. Thus, it could be argued that activation of deltai opioid receptors by endogenous enkephalins reduced endogenous CCK release, resulting in a decrease in CCKi receptor activation with subsequent reduction of the facilitatory effect of CCK system on opioid system, as CCKi activation seems to be essential for the potentiation of mu opioid analgesia [42,80]. 

Simantov R, Kuhar MJ, Uhl GR, Snyder SH (1977) Opioid peptide enkephalin immunohistochemical mapping in rat central nervous system. Proc Natl Acad Sci USA 74 2167-2171. 

In the 1970s, Hughes et al. were the first to show that two very different chemical structures have similar agonist properties (3). The opioid natural product, morphine (3), was found to resemble the N-terminal structure of the endogenous opioid peptides, enkephalins, (4a) and (4b), and j3-endorphin (5) (Fig. 15.2). The remarkable similarity between the morphine phenol system and the IV-terminal tyrosine residue in the peptide opioids implied that these units reacted with opioid receptors in a similar fashion to elicit comparable responses (4-6). 

Enkephalins are endogenous pentapeptides. Two enkephalins have been identified Met-enkephalin and Leu-enkephalin. Both enkephalins are relatively weak analgesics, which activate all opioid receptors but appear to have the highest affinity for the delta-receptors. In the central nervous system, enkephalins have been found in many areas, but predominantly those associated with nociception (Przewlocki and Przewlocka, 2001). 

Figure 8.2 The endogenous analgesic system. The three major components of the endogenous analgesic system include the periaqueductal gray matter in the midbrain nucleus raphe magnus in the medulla and pain inhibitory complex in the dorsal horns of the spinal cord. This system causes presynaptic inhibition of pain fibers entering the spinal cord. The binding of enkephalin to opioid receptors on the pain fibers prevents release of the neurotransmitter, substance P. As a result, the pain signal is terminated in the spinal cord and does not ascend to higher centers in the CNS.

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). 

The most potent and pervasive pain suppression system appears to be provided by endogenous opioids, particularly methionine encephalin and beta endorphin. These opioids and their receptors are widely distributed at several levels in the central nervous system (Mansour et al., 1988). Enkephalins appear to control the responses of dorsal horn neurons and may also modulate pain... 

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. 

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