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

Abstract

Oxytocin release from neurophypophysial terminals is particularly sensitive to inhibition by the micro-opioid receptor agonist, DAMGO. Because the R-type component of the neurophypophysial terminal Ca2+ current (ICa) mediates exclusively oxytocin release, we hypothesised that micro-opioids could preferentially inhibit oxytocin release by blocking this channel subtype. Whole-terminal recordings showed that DAMGO and the R-type selective blocker SNX-482 inhibit a similar ICa component. Measurements of [Ca2+]i levels and oxytocin release confirmed that the effects of DAMGO and SNX-482 are not additive. Finally, isolation of the R-type component and its associated rise in [Ca2+]i and oxytocin release allowed us to demonstrate the selective inhibition by DAMGO of this channel subtype. Thus, micro-opioid agonists modulate specifically oxytocin release in neurophypophysial terminals by selectively targeting R-type Ca2+ channels. Modulation of Ca2+ channel subtypes could be a general mechanism for drugs of abuse to regulate the release of specific neurotransmitters at central nervous system synapses.

Endogenous adenosine inhibits CNS terminal Ca2+ currents and exocytosis

“…The remaining tonic inhibition may be due to a build-up of other endogenous factors, such as opioids (Whitnall et al, 1983). It has already been shown that R-type transient calcium currents and OT release are inhibited by DAMGO, an opioid receptor agonist (Ortiz-Miranda et al, 2005), and that opioids are released from isolated neurohypophysial terminals (Bondy et al, 1988). In addition, since the A 1 receptor antagonist CPT has no effect on the transient Ca 2þ currents once the ecto-ATPase antagonist has been introduced, it is evident that the ''functional'' endogenous adenosine in these experiments is due to the breakdown of released ATP.…”

“…In addition, it has been shown that P2X ATP receptors are colocalized in isolated HNS terminals containing AVP but not OT (Knott et al, 2005). As there are also different channel subtypes in the two types of terminals (Wang et al, 1997(Wang et al, , 1999Ortiz-Miranda et al, 2005) it is, therefore, expected that the currents activated by the action potentials (APs) arriving at the terminals will be modulated differentially by the activation of purinoceptors. Thus, the existence of p2x receptors on AVP but not OT containing HNS terminals may help explain why there are different types of physiological bursting patterns controlling the release of the two peptide hormones (Lemos and Wang, 2000).…”

Role of Oxytocin in Prolactin Secretion during Late Pregnancy

“…However, a direct inhibitory opioid influence from arcuate nucleus POMC neurons may be also involved because a projection from these POMC neurons to the PVN and SON is well established [46,47]. On the other hand, NAL is a nonselective antagonist that acts on all subtypes of opioid receptors, so it may also act on the κ-opioid receptors located in the axon terminals of the neurohypophysis [48] that participate in the regulation of OT release [49], along with µ-opioid receptors that also act at this level [50,51].…”

Identification of the neuropeptide content of individual rat neurohypophysial terminals

“…Purinergic receptor (P2X) activation elicits inward cationic currents (Knott et al, 2005) that preferentially stimulate AVP release (Troadec et al, 1998). In contrast, -opioid receptor activation decreases depolarization induced OT release (Ortiz-Miranda et al, 2003) by preferentially inhibiting voltage dependent R-type calcium channels (Ortiz-Miranda et al, 2005).…”