Neuromodulatory actions of peptides.

Abstract

Before peptides were studied thoroughly in the nervous system, they were thought of as a new category of neurotransmitters. With time, it became clear that a given neuropeptide could be involved in a variety of biological func­ tions and that neurotransmitter-like actions alone were not enough to account for these functions. At the same time, it was found that many peptide actions had slow time courses (1-3); that there were mismatches between locations of peptides and their receptors in the brain (4); and that many neuropeptides coexisted with other transmitter agents in individual neurons (5,6). Assuming that neuromodulation includes a slow time course of action, a more diffuse site of action, and an ability to alter responses to transmitters (7), these findings strongly suggested that neuropeptides can serve as neuromodulators as well as neurotransmitters. Indeed, peptide neuromodulatory actions have been demonstrated by numerous studies. In the present review, we examine the characteristics, explore underlying mechanisms, and assess the biological and pharmacological significance of peptide neuromodulation. Because the term neuromodulation has been used in various ways, it is necessary to define the term here in order to limit the scope of the review (see also Refs. 8,9). In neuromodulation, as reviewed here (as distinguished from a synergistic or additive action), the modulator itself has no direct ef­ fect on the substrate or has an effect that is independent of the modula­ tion. The substrate whose response is measured can be a subcellular organ­ elle, a nerve, endocrine or muscle cell, a neural circuit, a transmitter sys­ tem, or an organ system. The effector whose direct action on the substrate