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

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Abstract
1 Using whole-cell patch clamp recording from neurones in an in vitro slice preparation, we have examined opioid- and orphanin FQ (OFQ)-mediated modulation 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 ≈50% of arcuate nucleus neurones and ≈95% of VMH neurones. The OFQ-activated current was blocked by the nociceptin antagonist [Phe1Ψ(CH2NH)Gly2]-nociceptin(1-13) NH2 (NCA), a peptide that on its own exhibited only weak agonist activity at high concentrations (> 1 μm). Similar current activation was observed with the μ agonist DAMGO but not δ (DPDPE) or κ (U69593) agonists. 3 In arcuate nucleus neurones, DAMGO (1 μm), U69593 (1 μm) and OFQ (100 nM to 1 μm) but not DPDPE (1 μm) were found to depress the amplitude of electrically evoked glutamatergic postsynaptic currents (EPSCs) and decrease the magnitude of paired-pulse depression, indicating that opioid receptors were located presynaptically. 4 In VMH neurones, DAMGO strongly depressed the EPSC amplitude in all cells examined. DAMGO decreased the magnitude of paired-pulse depression, indicating that μ receptors were located presynaptically. U69593 weakly depressed 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 μm), suggesting that the actions of μ receptors could be mediated by an inhibition of the synaptic vesicle release process downstream of Ca2+ entry. 6 The data presented show that presynaptic modulation of excitatory neurotransmission in the arcuate nucleus occurs through μ, κ and the orphan opioid ORL-1 receptors while in the VMH presynaptic modulation only occurs through μ opioid receptors. Additionally, postsynaptic μ and ORL-1 receptors in both the arcuate nucleus and VMH modulate neuronal excitability through activation of a K+ conductance.