Inhibition of Passive-Avoidance Memory Formation in the Day-Old Chick by the Opioid Cytochrophin-4

Abstract

Cytochrophin-4 (cyt-4), a tetrapeptide with opioid-like activity, caused amnesia when injected into chick forebrain 5 hr after passive-avoidance training. Bilateral injections of cyt-4 directly into the lobus parolfactorius (LPO) resulted in the chicks being amnesic for the training task 24 hr later, whereas unilateral injections of cyt-4 were effective only when injected into the right LPO. Cyt-4-induced amnesia was reversed by the general opioid antagonist, naloxone, indicating that cyt-4 was acting via an opioid receptor. The μ- and δ-opioid receptors (but not κ-opioid or ORL1-receptors) have been shown to be involved in memory formation 5 hr after training (Freeman and Young 2000). Because an antagonist of the μ-opioid receptor inhibited memory, we attempted to reverse the effect of cyt-4 using μ-opioid receptor agonists. Met[enk] was unable to reverse the inhibition of memory formation by cyt-4 suggesting that the μ-opioid receptor is not involved in this effect. However endomorphin-2 (endo-2) reversed the effect of cyt-4. We further investigated the action of endo-2 using an irreversible antagonist of the μ-receptor, β-funaltrexamine (β-FAN), and found that endo-2 reversed β-FAN-induced amnesia indicating that endo-2 was not acting on the μ-opioid receptor in the chick. Because unilateral injections of β-FAN were not amnesic (bilateral injections were amnesic) this provided further evidence that the effect of cyt-4 was not mediated via the μ-opioid receptor. Coinjection of the δ-receptor agonist, (D-Pen2, L-Pen5)enkephalin (DPLPE), reversed the disruptive effect of cyt-4 on memory. However, memory modulation via the δ-opioid receptor was not lateralized to the right hemisphere suggesting that cyt-4 does not act via this receptor either. It was shown that an antagonist of the ε-opioid receptor inhibited memory at the 5 hr time point. We conclude that the ε-opioid receptor or an unidentified opioid receptor subtype could be involved in the action of cyt-4.