Evidence for mu opioid receptor mediation of enkephalin-induced electroencephalographic seizures

The opioid receptor types involved in the mediation of enkephalin-induced electroencephalographic (EEG) seizures were studied in unanesthetized, freely moving rats. Four receptor-selective peptide ligands were evaluated for effectiveness in producing nonconvulsive EEG seizures after i.c.v. administration; these included the mu agonist, [D-Ala2-N-methyl-Phe4-Gly5-ol]enkephalin (DAGO), the mixed mu-delta agonist, [D-Ala2-D-Leu5]enkephalin (DADLE), and the selective delta agonists, [D-Pen2-D-Pen5]enkephalin and [D-Pen2-L-Pen5]enkephalin. Only DAGO and DADLE were found to produce EEG seizures, with DAGO being 9 times more potent than DADLE. DAGO produced a greater number of seizure episodes with a greater overall incidence compared with DADLE, reflecting its potent effect to elicit EEG seizure activity in these rats. Injections of [D-Pen2-D-Pen5]enkephalin or [D-Pen2-L-Pen5]enkephalin, even at the highest doses tested, failed to produce seizure activity. Behaviorally, the DAGO and DADLE EEG seizures were nonconvulsive but were temporally associated with episodic bursts of wet-dog shakes. The enkephalin-induced responses were extremely sensitive to antagonism by naloxone and completely blocked by pretreatment with the irreversible mu antagonist beta-funaltrexamine. The selective delta opioid receptor antagonist ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH) was ineffective. The use of the most selective agonists and antagonists for mu and delta opioid receptors suggests that, in rats, enkephalin-induced EEG seizures are mediated exclusively by mu opioid receptors and not by delta opioid systems.