Pre- and postsynaptic actions of opioid and orphan opioid agonists in the rat arcuate nucleus and ventromedial hypothalamus in vitro

1. Using whole-cell patch clamp recording from neurones in an in vitro slic e preparation, we have examined opioid- and orphanin FQ (OFQ)-mediated modu lation of synaptic transmission in the rat arcuate nucleus and ventromedial hypothalamus (VMH). 2. Application of OFQ activated a Ba2+-sensitive and inwardly rectifying K conductance in similar to 50% of arcuate nucleus neurones and similar to 9 5% of VMH neurones. The OFQ-activated current was blocked by the nociceptin antagonist [Phe(1)Psi(CH2NH)Gly(2)]-nociceptin(1-13) NH2 (NCA), a peptide that on its own exhibited only weak agonist activity at high concentrations (> 1 mu M). Similar current activation was observed with the mu agonist DA MGO but not delta (DPDPE) or kappa (U69593) agonists. 3. In arcuate nucleus neurones, DAMGO (1 mu M), U69593 (1 mu M) and OFQ (10 0 nM to 1 mu M) but not DPDPE (1 mu M) were found to depress the amplitude of electrically evoked glutamatergic postsynaptic currents (EPBCs) and decr ease the magnitude of paired-pulse depression, indicating that opioid recep tors were located presynaptically. 4. In VMH neurones, DAMGO strongly depressed the EPSC amplitude in all cell s examined. DAMGO decreased the magnitude of paired-pulse depression, indic ating that mu receptors were located presynaptically. U69593 weakly depress ed the EPSC while OFQ and DPDPE had no effect. 5. In VMH neurones, DAMGO depressed the frequency of miniature EPSCs (-58%) in the presence of tetrodotoxin and Cd2+ (100 mu M), suggesting that the a ctions of mu receptors could be mediated by an inhibition of the synaptic v esicle release process downstream of Ca2+ entry. 6. The data presented show that presynaptic modulation of excitatory neurot ransmission in the arcuate nucleus occurs through mu, kappa and the orphan opioid ORL-1. receptors while in the VMH presynaptic modulation only occurs through mu opioid receptors. additionally, postsynaptic mu and ORL-1 recep tors in both the arcuate nucleus and VMH modulate neuronal excitability thr ough activation of a K+ conductance.