µ‐Opioid Receptor Modulates Peptide Release From Rat Neurohypophysial Terminals By Inhibiting Ca²⁺ Influx

Abstract

The activation of opioid receptors in neurones of the central nervous system leads to a variety of effects including the modulation of diuresis and parturition, processes that are directly controlled by the hypothalamic-neurohypophysial system (HNS). The effects of mu-opioid receptor activation on peptide release, voltage-gated Ca2+ currents and intracellular calcium levels ([Ca2+]i) were studied in isolated nerve terminals of the HNS. The mu-receptor agonist, DAMGO ([d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin) inhibited high K+-induced peptide release in a dose-dependent manner, with oxytocin release being more sensitive to block than vasopressin release at all concentrations tested. The addition of the mu-receptor antagonist CTOP (d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr amide) was able to overcome the inhibitory effects of DAMGO. By contrast to previous results, voltage-gated Ca2+ currents were sensitive to blockage by DAMGO and this inhibition was also prevented by CTOP. Furthermore, [Ca2+]i measurements with Fura-2 corroborated the inhibition by DAMGO of calcium entry and its reversal by the micro -receptor antagonist in these nerve terminals. Thus, the decrease in neuropeptide release, particularly for oxytocin, induced by the activation of mu-opioid receptors in neurohypophysial terminals is mediated, at least in part, by a corresponding decrease in Ca2+ entry due to the inhibition of voltage-gated Ca2+ channels.

µ‐Opioid Receptor Preferentially Inhibits Oxytocin Release from Neurohypophysial Terminals by Blocking R‐type Ca2+ Channels

“…3), indicating that DAMGO is highly consistent in its selective targeting of this current component although, at higher concentrations, this agonist can also apparently affect other targets. In summary, we have shown that the l-opioid receptor agonist, DAMGO, preferentially inhibits oxytocin release induced by high K + from the neurohypophysis (20) and isolated hypothalamic-neurohypophysial system nerve terminals (21). We have also shown that voltage-gated R-type Ca 2+ channels, which are blocked by SNX482, regulate depolarisation-induced oxytocin but not AVP release from these isolated terminals (32).…”

The Effects of pH on Beta-Endorphin and Morphine Inhibition of Calcium Transients in Dorsal Root Ganglion Neurons

“…In addition, morphine-potentiated Ca 2ϩ responses to high-K ϩ (Ն100% of control) were excluded from analysis. 45 All data were analyzed by using a paired or unpaired t test as appropriate, with a 2-tailed P level of Ͻ.05 defining statistical significance. Data analysis was carried out by using Graphpad Prism software (Version 3; San Diego, Calif).…”

Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

“…1 The MOR interacts mostly with Ga i/o . 2 Following MOR activation, G protein-gated inwardly rectifying K + (GIRK) channels 3 open up while voltage-gated Ca 2+ channels (VGCC) 4 and intracellular adenylate cyclase-mediated cyclic adenosine monophosphate (cAMP) 5 production are inhibited. All of these cascades lead to membrane potential decrease, neuronal excitability, neurotransmitter release, and downstream signaling through their second messenger systems which ultimately affect gene expression.…”