Opioid related peptides are a group of endogenous neural polypeptides that bind especially to opiate receptors and mimic some of the pharmacological properties of opiates.
Chang in 1980 isolated a human genomic DNA segment encoding the corticotropin-ß-lipotropin precursor peptide from a fetal DNA library, using previously cloned bovine cDNA for this peptide as a probe. The human genomic DNA was studied by electron microscope heteroduplex analysis and gel blotting methods, and its nucleotide sequence was determined and compared with that of cDNA corresponding to bovine pro-opiomelanocortin (POMC) mRNA 1. The POMC gene codes for endogenous opiates, ß-endorphin and gamma-endorphin 2. Human enkephalins gene was isolated and its sequence described in 1982 by Noda 3. In 1983 human enkephalin B gene was isolated and sequenced 4.
The opioid peptide precursors are encoded by three genes: pre-proopiomelanocortin, pre-proenkephalin, and pre-prodynorphin. Each precursor is subjected to complex post-translational modifications that results in the synthesis of multiple active peptides. These peptides share the common N-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu), which has been termed the opioid motif; this is followed by various C-terminal extensions yielding peptides ranging from 5 to 31 residues in length. The major opioid peptide encoded by pre-proopiomelanocortin is ß-endorphin. In addition to ß- endorphin, the proopiomelanocortin precursor encodes the nonopioid peptides adrenocorticotropic hormone (ACTH), a-melanocyte-stimulating hormone (a-MSH), and ß-lipotropic pituitary hormone (ß-LPH). The isolation and primary structure of two peptides with morphinomimetic activity, obtained from an extract of porcine hypothalamus-neurohypophysis, are described. The amino acid sequence of the two peptides, named alpha-endorphin and gamma-endorphin, was determined by mass spectrometry and danxyl-Edman methods to be H-Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-OH and H-Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-OH, respectively. These correspond to the amino acid sequences present between residues 61 and 76 and residues 61 and 77 of the various ß-lipotropins. A third peptide also obtained in pure form in these studies was found to be an unstable salt of a-endorphin 5. The primary structure of porcine preproenkephalin B has been elucidated by cloning and sequencing cDNA: it contains neoendorphin, dynorphin and leumorphin (containing rimorphin as its amino-terminus). These opioid peptides, each having a leucine-enkephalin structure, act on the kappa-receptor 4. H - Leu - Val - Val - Tyr - Pro - Trp - Thr - Gln - Arg – OH, peptide is amino acids 32 to 40 fragment of the ß, d,?, and ?-chains of human hemoglobin. It possesses some opiate activity. This peptide was isolated from the pituitary gland5.
Mode of Action
Opioid peptides and their G-protein-coupled receptors (d, ?, µ) are located in the central nervous system and peripheral tissues. The opioid system has been studied to determine the intrinsic mechanism of modulation of pain and to develop uniquely effective pain-control substances with minimal abuse potential and side effects. Two types of endogenous opioid peptides exist, one containing Try-Gly-Gly-Phe as the message domain (enkephalins, endorphins, dynorphins) and the other containing the Tyr-Pro-Phe/Trp sequence (endomorphins-1 and -2). Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has high mu receptor affinity (Ki = 0.36 nM) and remarkable selectivity (4000- and 15,000-fold preference over the d and ? receptors, respectively). In addition, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), isolated from the same sources, exhibited high mu receptor affinity (Ki = 0.69 nM) and very high selectivity (13,000- and 7500-fold preference relative to d and ? receptors, respectively). Both opioids bind to µ-opioid receptors, thereby activating G-proteins, resulting in regulation of gastrointestinal motility, manifestation of antinociception, and effects on the vascular systems and memory. To develop novel analgesics with less addictive properties, evaluation of the structure-activity relationships of the endomorphins led to the design of more potent and stable analgesics. Opioidmimetics and opioid peptides containing the amino acid sequence of the message domain of endomorphins, Tyr-Pro-Phe/Trp, exhibit unique binding activity and lead to the development of new therapeutic drugs for controlling pain 6.
Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, and the control of food intake.
Endogenous opioid systems play a critical role in modulating a large number of sensory, motivational, emotional, and cognitive functions 7.
As inhibitory neuropeptide transmitters, endogenous opioid peptides fine-tune neurotransmission across a wide range of neuronal circuits, setting thresholds or upper limits. the regulation of pain responsiveness as one example of a function mediated by opioids to illustrate the complexity of their role.
Milk proteins are potential sources of opioid agonistic and antagonistic peptides. Milk protein derived opioid peptides have been designated as `atypical' opioid peptides. Opioid peptides, i.e. opioid receptor ligands with agonistic activity, originate from different milk proteins and exert naloxone-inhibitable opioid activities in both receptor studies and during bioassays 8.
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