The novel micro-opioid receptor antagonist, [N-allyl-Dmt(1)]endomorphin-2, attenuates the enhancement of GABAergic neurotransmission by ethanol.
OBJECTIVE
We investigated the effects of [N-allyl-Dmt(1)]endomorphin-2 (TL-319), a novel and highly potent micro-opioid receptor antagonist, on ethanol (EtOH)-induced enhancement of GABA(A) receptor-mediated synaptic activity in the hippocampus.


METHODS
Evoked and spontaneous inhibitory postsynaptic currents (eIPSCs and sIPSCs) were isolated from CA1 pyramidal cells from brain slices of male rats using whole-cell patch-clamp techniques.


RESULTS
TL-319 had no effect on the baseline amplitude of eIPSCs or the frequency of sIPSCs. However, it induced a dose-dependent suppression of an ethanol-induced increase of sIPSC frequency with full reversal at concentrations of 500 nM and higher. The non-specific competitive opioid receptor antagonist naltrexone also suppressed EtOH-induced increases in sIPSC frequency but only at a concentration of 60 microM.


CONCLUSIONS
These data indicate that blockade of micro-opioid receptors by low concentrations of [N-allyl-Dmt(1)]endomorphin-2 can reverse ethanol-induced increases in GABAergic neurotransmission and possibly alter its anxiolytic or sedative effects. This suggests the possibility that high potency opioid antagonists may emerge as possible candidate compounds for the treatment of ethanol addiction.
Li
Qiang
Q
Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA.
Okada
Yoshio
Y
Marczak
Ewa
E
Wilson
Wilkie A
WA
Lazarus
Lawrence H
LH
Swartzwelder
H S
HS
D000818:Animals; D002492:Central Nervous System Depressants / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D007700:Kinetics; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
C538778:(N-allyl-Dmt(1))endomorphin-2; D002492:Central Nervous System Depressants; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; D000431:Ethanol; C105294:endomorphin 2; D005680:gamma-Aminobutyric Acid