Peripheral modulation of learning and memory: enkephalins as a model system.

Extensive research on the effects of enkephalins on conditioning is reviewed and used as the basis for a model of peripheral modulation of learning and memory. An overall theme emphasized throughout our discussion is that these peptides can influence the strength with which a memory is acquired and stored by acting outside the blood-brain barrier. This assertion is supported by research on the behavioral effects of systemically administered enkephalins and opioid antagonists, the rapid hydrolysis of circulating enkephalins in vivo, and the limited ability of these peptides to penetrate the blood-brain barrier. A consideration of the extensive distribution of enkephalins throughout peripheral autonomic systems leads to the proposal that enkephalins may act to modulate learning and memory by altering peripheral autonomic function; autonomic afferents may then communicate with the memory trace in the CNS through a central modulatory pathway outlined herein. Evidence that some stressful experiences may lead to increases in circulating enkephalins also is discussed. The sites of action of these circulating enkephalins may involve peripheral autonomic sites, or additionally may involve the circumventricular organs. As a further regulatory mechanism, circulating enkephalin levels may be controlled by experience-dependent alterations of the activity of enzyme systems that participate in their breakdown. Finally, it is emphasized that the mechanisms of enkephalin action postulated herein may be applicable to the actions of other peripheral hormones, peptides, and neurotransmitters that participate in the modulation of learning and memory storage processes.