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µ-Opioid receptor activation inhibits N- and P-type Ca²⁺ channel currents in magnocellular neurones of the rat supraoptic nucleus

Brandi L. Soldo and Hylan C. Moises

The whole-cell voltage-clamp technique was used to examine opioid regulation of Ba²⁺ currents (I_Ba) through voltage-sensitive Ca²⁺ channels in isolated magnocellular supraoptic neurones (MNCs). The effects of local application of µ-, - or -opioid receptor selective agonists were examined on specific components of high voltage-activated (HVA) I_Ba, pharmacologically isolated by use of Ca²⁺ channel-subtype selective antagonists.

The µ-opioid receptor selective agonist, DAMGO, suppressed HVA I_Ba (in 64/71 neurones) in a naloxone-reversible and concentration-dependent manner (EC₅₀ = 170 nM, E_max = 19·5 %). The DAMGO-induced inhibition was rapid in onset, associated with kinetic slowing and voltage dependent, being reversed by strong depolarizing prepulses. Low-voltage activated (LVA) I_Ba was not modulated by DAMGO.

Administration of - (U69 593) or -selective (DPDPE) opioid receptor agonists did not affect I_Ba. However, immunostaining of permeabilized MNCs with an antibody specific for ₁-opioid receptors revealed the presence of this opioid receptor subtype in a large number of isolated somata.

µ-Opioid-induced inhibition in I_Ba was largely abolished after blockade of N-type and P-type channel currents by -conotoxin GVIA (1 µM) and -agatoxin IVA (100 nM), respectively. Quantitation of antagonist effects on DAMGO-induced reductions in I_Ba revealed that N- and P-type channels contributed roughly equally to the µ-opioid sensitive portion of total I_Ba.

These results indicate that µ-opioid receptors are negatively coupled to N- and P-type Ca²⁺ channels in the somatodendritic regions of MNCs, possibly via a membrane-delimited G-protein-dependent pathway. They also support a scheme in which opioids may act in part to modulate cellular activity and regulate neurosecretory function by their direct action on the neuroendocrine neurones of the hypothalamic supraoptic neucleus.

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