Concepts for biologically active peptides

Abstract

Here we review a unique aspect of CNS research on biologically active peptides that started against a background of prevalent dogmas but ended by exerting considerable influence on the field. During the course of refuting some doctrines, we introduced several concepts that were unconventional and paradigm-shifting at the time. We showed that (1) hypothalamic peptides can act 'up' on the brain as well as 'down' on the pituitary, (2) peripheral peptides can affect the brain, (3) peptides can cross the blood-brain barrier, (4) the actions of peptides can persist longer than their half-lives in blood, (5) perinatal administration of peptides can exert actions persisting into adulthood, (6) a single peptide can have more than one action, (7) dose-response relationships of peptides need not be linear, (8) the brain produces antiopiate as well as opiate peptides, (9) there is a selective high affinity endogenous peptide ligand for the mu-opiate receptor, (10) a peptide's name does not restrict its effects, and (11) astrocytes assume an active role in response to metabolic disturbance and hyperleptinemia. The evolving questions in our laboratories reflect the diligent effort of the neuropeptide community to identify the roles of peptides in the CNS. The next decade is expected to see greater progress in the following areas: (a) interactions of peptides with other molecules in the CNS; (b) peptide involvement in cell-cell interactions; and (c) peptides in neuropsychiatric, autoimmune, and neurodegenerative diseases. The development of peptidomics and gene silencing approaches will expedite the formation of many new concepts in a new era.

Fig. 1

The inverted-U shaped dose-response curve seen in investigations by R.H. Ehrensing et al. of the effects of oral MIF-1 in patients with mental depression.

Fig. 2

Demonstration that the electrophysiological effects of an analog of the opiate Met-enkephalin (enkephalin peptide) administered peripherally can be blocked by an opiate antagonist (naltexone) that crosses the bloodbrain barrier but not by an opiate antagonist (methyl naltrexone) that does not readily cross the blood-brain barrier (modified from Kastin et al. [72]).