Central versus peripheral actions of Leu-enkephalin on acquisition of a one-way active avoidance response in rats

doi:10.1016/0006-8993(85)91496-9

Brain Research

Volume 327, Issues 1–2, 18 February 1985, Pages 37-43

https://doi.org/10.1016/0006-8993(85)91496-9 Get rights and content

Abstract

A comparison was carried out of the effectiveness of intracerebroventricular or intraperitoneal administration of Leu-enkephalin to affect acquisition of a one-way active avoidance response, locomotor activity or shock sensitivity. Leu-enkephalin impaired acquisition of the avoidance response only when administered peripherally. In contrast, either central or peripheral administration of Leu-enkephalin increased locomotor activity in the open field, and Leu-enkephalin also produced analgesia when administered directly into the brain. The pattern of results suggests that Leu-enkephalin acts at a peripheral site to influence avoidance conditioning.

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Cited by (23)

Experience-dependent regulation of Leu-enkephalin hydrolysis in rat plasma
1993, Peptides
We examined experience-dependent alterations in the production of individual enkephalin metabolites during Leu-enkephalin hydrolysis in rat plasma in vitro. High performance liquid chromatography separation and electrochemical detection were used to quantify accumulation of the primary $N- terminal$ products of enkephalin hydrolysis, Tyr and Tyr-Gly-Gly. Blood was sampled from rats through indwelling femoral artery catheters before, during, and after active avoidance training or appropriate control treatments. Avoidance training increased Tyr production, as did handling and exposing animals to the novel avoidance chamber without foot-shock training. On the other hand, Tyr-Gly-Gly production was elevated by blood sampling alone, by handling/novelty, and by training, but the effect of training was significantly greater than the effects of either of the other treatments. Interestingly, Tyr-Gly-Gly production was highly correlated ( $r = −0.885$ ) with a measure of escape performance. Since the enzymes that participate in enkephalin hydrolysis act upon a number of peptides, regulation of enzyme activity may be one mechanism whereby an organism can modulate levels of circulating peptides in response to environmental experiences; this may contribute to the expression of appropriate behavioral responses to those environmental experiences.
Adrenalectomy attenuates the improvement of memory in rats by peripheral application of des-Tyr-d-Pro4-casomorphin
1993, Behavioral and Neural Biology
β-Casomorphin derivatives without the N-terminal amino acid tyrosine possess memory-improving effects after central and peripheral application. We investigated the significance of adrenal glands for the memory improving effect of the systemically applied β-casomorphin derivative des-Tyr-d-Pro⁴CM (Pro-Phe-d-Pro-Gly) in a learning experiment. Seven-week-old rats were adrenalectomized or sham operated. One week after surgery the rats were trained in an active avoidance task in a shuttle box. Five avoidance reactions were taken as learning criterion. After training 10 nmol/kg des-Tyr-d-Pro⁴CM or saline (10 ml/kg) was subcutaneously applied. There were no differences in acquisition between adrenalectomized and sham-operated rats. The memory retention of shamoperated animals was improved by des-Tyr-d-Pro⁴CM. In adrenalectomized rats this positive effect could not be observed. The involvement of adrenal glands in the peptide effect during learning and retention is discussed.
d-Pen2-[d-Pen5]Enkephalin impairs acquisition and enhances retention of a one-way active avoidance response in rats
1992, Peptides
We reported previously that d-Pen²-[d-Pen⁵]enkephalin (DPDPE), a δ-opioid receptor selective analog of Leu-enkephalin, impairs acquisition of an automated jump-up avoidance response in rats and acquisition of a one-way active avoidance response in mice. In the present study we investigated the effects of DPDPE on one-way avoidance conditioning in rats. The rats received two escape-only trials on day 1 and eight additional training trials on day 2. DPDPE (1.16 μg/kg IP) administered prior to training on day 2 impaired acquisition of the avoidance response. On the other hand, DPDPE (0.332 μg/kg IP) administered following presentation of the two escape-only trials on day 1 significantly enhanced retention, as measured by improved one-way active avoidance performance on day 2. These results indicate that activation of δ-opioid receptors by DPDPE has a modulatory effect on acquisition and retention of aversively motivated performance.
[Leu]enkephalin and its metabolite, Tyr-Gly-Gly, impair active avoidance retention
1992, Pharmacology, Biochemistry and Behavior
The current study examined the effects of [leu]enkephalin and its metabolite, Tyr-Gly-Gly, given immediately posttraining on active avoidance performance measured 24 h later. Initial experiments revealed that, in comparison to zero or one training trials, providing mice with two training trials significantly increased active avoidance performance measured 24 h later; this enabled us to examine the effects on retention of peptides administered immediately after the two training trials. It was found that Tyr-Gly-Gly (16 and 53 μg/kg) and [leu]enkephalin (30 and 100 μg/kg) administered in this fashion both significantly impaired retention; the dose-response functions for both peptides were U-shaped. Since the effects of enkephalins are most likely mediated by opioid δ-receptors, and Tyr-Gly-Gly has little or no activity at opioid receptors, the effects of the parent peptide(s) and metabolite are presumably pharmacologically distinct.
Uptake and metabolism of [3H]-Leu-enkephalin following either its intraperitoneal or subcutaneous administration to mice
1992, Peptides
The uptake and metabolism of 30 μg/kg [³H]-Leu-enkephalin ([³H]-LE) following either intraperitoneal (IP) or subcutaneous (SC) administration to Swiss Webster mice was examined. Uptake of [³H] was rapid, with peak levels of radioactivity in plasma observed at 5 or 10 min following IP or SC peptide injection, respectively. The majority ( $80–99% ± 0.8$ ) of plasma radioactivity at all postinjection plasma collection time points was in the form of tyrosine-containing enkephalin metabolites, indicating a substantial and rapid in vivo hydrolysis rate for exogenously administered LE. Leu-enkephalin is metabolized in vivo faster than previously reported in vitro in mouse plasma. However, despite this extensive hydrolysis, levels of intact LE remaining in plasma following its systemic administration are within or above endogenous LE plasma levels.
Only tyrosine-containing metabolites of [Leu]Enkephalin impair active avoidance conditioning in mice
1990, Pharmacology, Biochemistry and Behavior
The effects of the enkephalin metabolites, Tyr, des-Tyr-[Leu]enkephalin (GGFL), and Tyr-Gly-Gly (YGG), on acquisition of an active avoidance task following their IP administration to mice were determined. Neither free Tyr (3.9–390.0 μg/kg) nor GGFL (7.1–710.0 μg/kg) altered acquisition of the avoidance response. In contrast, 53, but not 16 μg/kg, of YGG significantly impaired response acquisition. A 390.0, but not 39.0 μg/kg, dose of Tyr decreased locomotor activity levels measured in an open field. Together with previous findings that the enkephalin metabolites Tyr-Gly and Tyr-Gly-Gly-Phe also impair avoidance acquisition, these data indicate that the dipeptide Tyr-Gly is the minimum sequence needed to intefere with acquisition of an active avoidance response. Because the various enkephalin metabolites do not bind to opioid receptors, it is likely that their effects on avoidance acquisition represent a separate class of pharmacological agents whose effects are mediated by a nonopioid receptor mechanism. These results are important to the interpretation of behavioral studies involving peripheral administration of the opioid peptide, [Leu]enkephalin (LE).

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^*: Present address for R. C. Dana

^**: The data reported in this paper were presented in part at the 13th Annual Meeting of the Society for Neuroscience, Boston, MA, November, 1983 (ref. 12).

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Brain Research

Abstract

References (29)

Facilitation of long-term memory by brain endorphins

Actions of ACTH- and MSH-like peptides on learning, performance, and retention

Retrograde amnesia caused by Met-, Leu- and des-Tyt-Met-enkephalin in the rat and its reversal by naloxone

Neurosci. Lett.

Behavioral activation by enkephalins in mice

Pharmacol. Biochem. Behav.

Systemic administration of Met-enkephalin, [d-Ala²]-Met-enkephalin, β-endorphin; effects on eating, drinking, and activity measures in rats

Pharmacol. Biochem. Behav.

Intracerebroventricular administration of nanogram amounts of β-endorphin and Met-enkephalin causes retrograde amnesia in rats

Behav. Brain Res.

Central and peripheral actions of amphetamine on memory storage

Brain Research

Modulation of memory processes induced by stimulation of the entorhinal cortex

Physiol. Behav.

Enkephalin actions on avoidance conditioning may be related to adrenal medullary function

Behav. Brain Res.

Endorphin and enkephalin effects on avoidance conditioning: the other side of the pituitary-adrenal axis

Influence of β-lipotropin fragments on responsiveness of rats to electric footshock

Pharmacol. Biochem. Behav.

Enkephalins interfere with acquisition of an active avoidance response

Life Sci.

Kyotorphin (L-TYR-L-ARG) inhibits extinction of pole-jumping avoidance response in the rat

Neurosci. Lett.

Opioid peptides in adrenal gland

Life Sci.

Cited by (23)

Experience-dependent regulation of Leu-enkephalin hydrolysis in rat plasma

Adrenalectomy attenuates the improvement of memory in rats by peripheral application of des-Tyr-d-Pro<sup>4</sup>-casomorphin

d-Pen<sup>2</sup>-[d-Pen<sup>5</sup>]Enkephalin impairs acquisition and enhances retention of a one-way active avoidance response in rats

[Leu]enkephalin and its metabolite, Tyr-Gly-Gly, impair active avoidance retention

Uptake and metabolism of [<sup>3</sup>H]-Leu-enkephalin following either its intraperitoneal or subcutaneous administration to mice

Only tyrosine-containing metabolites of [Leu]Enkephalin impair active avoidance conditioning in mice