Inhibition of passive-avoidance memory formation in the day-old chick by the opioid cytochrophin-4

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 mu- and delta-opioid receptors (but not kappa-opioid or ORL(1)-receptors) have been shown to be involved in memory formation 5 hr after training (). Because an antagonist of the mu-opioid receptor inhibited memory, we attempted to reverse the effect of cyt-4 using mu-opioid receptor agonists. Met[enk] was unable to reverse the inhibition of memory formation by cyt-4 suggesting that the mu-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 mu-receptor, beta-funaltrexamine (beta-FAN), and found that endo-2 reversed beta-FAN-induced amnesia indicating that endo-2 was not acting on the mu-opioid receptor in the chick. Because unilateral injections of beta-FAN were not amnesic (bilateral injections were amnesic) this provided further evidence that the effect of cyt-4 was not mediated via the mu-opioid receptor. Coinjection of the delta-receptor agonist, (D-Pen(2), L-Pen(5))enkephalin (DPLPE), reversed the disruptive effect of cyt-4 on memory. However, memory modulation via the delta-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 epsilon-opioid receptor inhibited memory at the 5 hr time point. We conclude that the epsilon-opioid receptor or an unidentified opioid receptor subtype could be involved in the action of cyt-4.