Neuropeptides and Monoaminergic Neurotransmitters: Their Relation to Pain

Abstract

The discovery of oligopeptides, short chains of amino acids, in the normal central nervous system (CNS) has added a new and at present bewildering scope to our awareness of how the brain and spinal cord regulate their own activity. Precise localizations of these substances have followed the identification of the amino acid sequence of each peptide, the relative ease with which each is synthesized, and the development of progressively more specific antibOdies to each peptide conjugated to a carrier protein as antigen. Two powerful neuroanatomical techniques are in use: (I) Immunocytochemical methods permit light microscopy by the indirect fluorescent technique of Coons (1958),or by the peroxidase-antiperoxidase method of Sternberger (1974) and Moriarty (1973). The addition of osmic acid to the latter method increases the electron density of the reaction products and permits electron microscopy to show details of peptide relationships in the subcellular organelles. The immunoreactive staining does not, however, increase in linear fashion with increased concentration of the peptide. (2) Radioimmunoassay does yield quantitative data on concentrations of peptide in frozen specimens of CNS identified and excised under operative microscopy (Kobayashi et al. 1977). The commonest radiolabels are 3H and 1251. The British investigators Hughes and Kosterlitz of Aberdeen, the Iversens and their collaborators at the University of Cambridge, the groups of Hokfelt of Stockholm, Leeman of Boston and Snyder of Baltimore have made many of these major discoveries.One of the most clear-cut features of the new data is that nearly every one of these peptides is concentrated at such diverse sites as to connote widely varying functions for each of them. Conversely, each function has associated with it an astounding number of different peptides. To illustrate these points,

Gastrin Levels in Patients with Migraine and Cluster Headache

“…So far, it is difficult to decide whether the gastrin level decrease is a result of alimentary canal disturbances or is this relation at the CNS level, because the inter dependences of the gastrin level in brain and at the periphery are not yet fully evaluated. Similar distribution of gastrin and cholecystokinin in the brain [3,5] allows to suppose that gastrin can also take part in pain sensa tion modulation similarly to other neuropep tides [1,6]. This could correspond with the low level of this hormone in migraine and cluster headache sufferers.…”

Clinical pharmacology in the last decade

“…Radioimmunoassay and immunocytochemical techniques have shown that some peptides first identified in the gut wall, such as vasoactive intestinal polypeptide (VIP) and cholecystokinin are also found in the brain. Releasing and release-inhibiting factors first identified in the hypothalamus, such as thyrotrophin releasing hormone (TRH) and somatostatin have been found to have wider central nervous distribution (Sweet, 1980;Editorial, 1980). Limited human studies and much animal evidence suggest that these peptides have roles in the control of behaviour, emotions, sex and sleep.…”

“…Pharmacologists had, therefore, sought for the brain's own endogenous ligand for which these receptors had evolved, and it was the Aberdeen group under Kosterlitz and Hughes who first identified the 2 similar pentapeptides metand leu-enkephalin, and showed that met-enkephalin had the same amino acid sequence of a larger peptide, 3-endorphin (Tregear and Coghlan, 1980). The enkephalins are rapidly degraded by peptidases and therefore analogues which have longer activity have been studied in man, but so far their adverse effects have predominated over any potential therapeutic activity (Sweet, 1980). The relationship of Pendorphin to pain relief in man has been demonstrated by its increase in human third ventricular cerebrospinal fluid after electrical stimulation in the thalamus that produced marked or complete relief of severe pain (Sweet, 1980), and after acupuncture (Clement-Jones et al, 1980;Anzhong et al, 1980).…”

“…The enkephalins are rapidly degraded by peptidases and therefore analogues which have longer activity have been studied in man, but so far their adverse effects have predominated over any potential therapeutic activity (Sweet, 1980). The relationship of Pendorphin to pain relief in man has been demonstrated by its increase in human third ventricular cerebrospinal fluid after electrical stimulation in the thalamus that produced marked or complete relief of severe pain (Sweet, 1980), and after acupuncture (Clement-Jones et al, 1980;Anzhong et al, 1980). Enkephalins and endorphins do not appear to be limited in their pharmacological actions to an involvement in pain relief, however.…”

Cyclic AMP regulates substance P expression in developing and mature spinal sensory neurons

“…The tachykinin, substance P, has long been associated with transmission of noxious stimuli (Marx, 1979;Sweet, 1980) based on a number of observations including: (a) its distribution in the neuraxis to areas known to be involved with pain transmission (Hokfelt et al, 1976;Hunt et al, 1981); (b) its unique occurrence in dental tooth pulp, a tissue commonly known to be exquisitely pain-sensitive (Olgart et al, 1977); (c) the pain in response to application of capsaicin, a naturally occurring alkaloid that induces substance P release (Yaksh et al, 1979); and (d) nociceptive behavior observed in freely moving animals after substance P application (Hylden and Wilcox, 1981). In the peripheral nervous system, substance P is localized to small C-fiber type neurons in the dorsal root ganglion (DRG) which project centrally to the substantia gelatinosa (Hokfelt et al, 1976;Hunt et al, 1981).…”