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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 circum-ventricular 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. [ABSTRACT FROM AUTHOR]

The effects on one-way active avoidance conditioning of pre-training, systemic administration of the selective μ-receptor agonist [ d-Ala,N-Me-Phe, Glyol]enkephalin (DAGO), and the selective μ-receptor antagonist ( d-Phe-Cys-Tyr- d-Trp-Orn-Thr-Pen-Thr-NH (CTOP), were determined in Swiss-Webster mice. A low dose of DAGO (0.92 µg/kg) moderately enhanced avoidance acquisition, whereas a 100 µg/kg dose of CTOP more dramatically impaired acquisition. However, the avoidance-enhancing dose of DAGO significantly increased locomotor activity as measured in a separate group of mice in the avoidance chamber, and the avoidance-impairing dose of CTOP significantly decreased activity. Under these same training conditions, earlier studies (Schulteis et al. 1988; Schulteis and Martinez 1990) demonstrated that enkephalins impaired avoidance learning, and selective δ-receptor antagonists such as ICI 174,864 enhanced learning; in contrast to the present study, both of these effects were dissociated from performance effects such as alterations in locomotor activity. Taken together, the results suggested that the effects of enkephalins were mediated by the δ-, but not μ-, class of opioid receptor. [ABSTRACT FROM AUTHOR]

The role of opioid delta receptors in the learning impairment produced by [leu]enkephalin (LE) in one-way active avoidance conditioning was investigated in mice. LE (30 and 100 µg/kg) impaired acquisition of the avoidance response, whereas ICI 174,864 (3.0 mg/kg), a selective delta opioid receptor antagonist, enhanced acquisition. The impairment produced by 100 µg/kg LE was completely reversed by 1.0 mg/kg ICI 174,864, a dose of the antagonist that by itself had no effect. Control studies provided evidence that the effects of ICI 174,864 and LE on conditioning cannot be explained by performance variables such as alterations in activity levels or footshock sensitivity. The results suggest that opioid delta receptors play an important role in the modulation of learning, and that the effects of LE on avoidance conditioning are mediated by delta receptors. [ABSTRACT FROM AUTHOR]

Graded doses of sodium nitrite were administered shortly before or immediately after a single training trial in an inhibitory avoidance task. A retention test was given at 24 h (rats) or 72 h (mice) after training. The results indicate that sodium nitrite impairs acquisition of an inhibitory avoidance response in rats and mice. Retention was impaired with doses lower than those required for producing hypoxic effects, as measured by the EEG, methemoglobin levels in the blood, blood pressure, and heart rate. Since hypoxia was not involved, it is likely that the effects were mediated by some direct action of sodium nitrite on the CNS. [ABSTRACT FROM AUTHOR]