Morfina inibe corrente mediada por receptores mGluR-I em neurônios do Locus Coeruleus

Abstract

Locus Coeruleus (LC) neurons express several types of G-protein coupled receptors that regulate their cellular excitability and, consequently, the liberation of noradrenaline throughout the central nervous system. This study presents a comparison of the relative strength of two of these receptors that have opposite effects on excitability: Group I mGluR (mGluR-I) receptors and μ-opioid receptors (μ). As expected, based on many previous studies, morphine (5 μM) hyperpolarized LC neurons, and this effect was antagonized by the selective μ inverse agonist naloxone. This well-known effect of morphine is mediated by opioid receptors that activate KIR-type potassium channels. Subsequent application of the mGluR-I agonist, DHPG (30 μM) in the presence of morphine completely reversed the inhibitory action of μ. The possibility that the two receptors exert their opposite effects through a common mechanism mediated by KIR-type potassium channels was tested in two ways: i) by examining changes in membrane conductance associated with receptor activation and ii) by examining the I-V relationship of the underlying currents. Both approaches failed to provide evidence for a common mechanism. During the experiments, we observed a surprising functional interaction between the receptors in those currents evoked by DHPG and measured under voltage clamp were smaller in the presence of morphine than in control conditions. Further voltage clamp experiments using ramp protocols again confirmed that this interaction was not mediated by potassium channels. The results reveal a previously unknown interaction between two receptors that exert a strong antagonistic modulatory influence on the activity of the Locus Coeruleus neurons.