Endogenous opioid peptides and the control of pain

TLDR: The investigation of the analgesic, or rather antinociceptive, properties of the opioid peptides is made difficult by the high sensitivity of the pentapeptides, the enkephalins, to the very rapid degrading actions of aminopeptidase and carboxypeptidases.

Abstract: In recent years it has become evident that peptides of relatively small molecular weight play an important role not only in the regulation of endocrine function but also in the control of certain pathways in the central nervous system. The discovery of peptides which mimic the actions of morphine is of particular interest since it may give an insight into the physiological modulation of responses to painful experiences. Two such pentapeptides, methionine-enkephalin (tyrosineglycine-glycine-phenylalanine-methionine) and leucine-enkephalin (tyrosine-glycine-glycine-phenylalanine-leucine) were identified in extracts of pig brains (Hughes et al. 1975) and of other species. It is of interest that the sequence of methionine-enkephalin is present in the pituitary peptide filipotropin as amino acid residues 61-65. Present evidence indicates that there are 2 independent peptidergic systems: one is characterized by the presence of the short-chain peptides, methionine-enkephalin and leucine-enkephalin, and is widespread throughout the central and peripheral nervous systems (Elde et al. 1976; Hughes et al. 1977; Simantov et al. 1977), whereas the other system contains the long-chain peptide, /?-endorphin (/Wipotropine^gj) and is centred around the hypothalamus-pituitary axis with extensions into the thalamus, midbrain, medulla and pons (Rossier et al. 19776). The investigation of the analgesic, or rather antinociceptive, properties of the opioid peptides is made difficult by the high sensitivity of the pentapeptides, the enkephalins, to the very rapid degrading actions of aminopeptidases and carboxypeptidases, whereas the long-chain peptides are resistant to these enzymes and have their activity more slowly reduced by an endopeptidase cleaving the molecule between amino acid residues 77 and 78. This property of the enkephalins makes the use of the ordinary antinociceptive tests unreliable, even if the peptides are administered directly into the cerebral ventricles. On the other hand, /?-endorphin is a very strong and long-lasting antinociceptive agent (Feldberg & Smyth, 1977), even after intravenous administration to mice but not to rats (Tseng etal. 1976; Rossier etal. 1977a). In this context it is of interest that the affinity of /?-endorphin to the receptor represented by [H]leucine-enkephalin or [H]methionine-enkephalin binding in brain homogenate is similar to that of methionine-enkephalin and leucine-enkephalin, whereas its affinity to the receptor represented by [H]naloxone or [H]naltrexone binding is considerably greater than that of methionine-enkephalin and particularly of leucine-enkephalin. In contrast to the opioid peptides, morphine has a much lower affinity to the binding site of [H]leucine-enkephalin than to that of [H]naloxone or [H]naltrexone (Lord et al. 1977). The evidence that methionine-enkephalin and possibly leucine-enkephalin play an important role in the control of the modulation of the transmission of noxious and painful stimuli is based on electro-physiological experiments, on the relationship between substance P and enkephalin in the central nervous system and the antagonism by naloxone of the analgesic effects of electrical stimulation of the pericentral grey in intractable pain and of those of electro-acupuncture. It has been shown (Duggan et al. 1977) that methionine-enkephalin and its amide have different effects on the responses of neurones of spinal laminae IV and V of spinal cats to noxious and innocuous skin stimuli. When administered in the substantia gelatinosa, the enkephalins predominantly reduce the responses to noxious stimuli with little effect on the responses to nonnociceptive stimuli. These observations are in good agreement with the immunohistochemical findings that methionine-enkephalin and substance P have a similar distribution in areas related to pain and analgesia (Hokfelt et al. 1977). Such areas are the periaqueductal grey, the marginal layer of the spinal trigeminal nucleus and the substantia gelatinosa of the dorsal horn of the spinal cord