Opioid tolerance and dependence in the magnocellular oxytocin system: a physiological mechanism?

Abstract

At the neurosecretory terminals in the neural lobe, oxytocin secretion is restrained by co‐secreted endogenous opioids, which act via kappa‐receptors. The co‐secreted opioids include products of pro‐dynorphin (released by both vasopressin and oxytocin terminals) and proenkephalin (released by oxytocin terminals). In morphine‐tolerant rats this opioid mechanism is more effective, but in late pregnancy it is less effective. Opioids also act directly on oxytocin cell bodies, via separate mu‐ and kappa‐receptors, inhibiting excitation by all stimuli tested, and also exert presynaptic and more distal actions on afferent systems. During chronic morphine exposure, tolerance and dependence develop in oxytocin neurones; the former involves reduction in mu‐opioid receptor density, while the latter may involve compensatory upregulation of mechanisms regulating Ca2+ influx. In mid‐pregnancy, the effectiveness of opioid mechanisms in the neural lobe increases, assisting the accumulation of oxytocin stores in advance of parturition, but by the end of pregnancy the effectiveness of these mechanisms is reduced. At this time, a separate endogenous opioid system, acting via mu‐receptors, actively restrains the electrical activity of oxytocin neurones. Release of this endogenous opioid inhibition may contribute to the increase in activity during parturition analogous to that occurring during morphine withdrawal excitation. Central opioid mechanisms retain the ability to control oxytocin neurones during parturition, and can interrupt established parturition by inhibiting oxytocin neurone firing rate in disadvantageous environmental circumstances.

κ-Opioid Receptor Activation Modulates Ca2+Currents and Secretion in Isolated Neuroendocrine Nerve Terminals

“…Our finding in a few terminals that administration of -opioids attenuated depolarization-evoked C m responses despite little or no decrease in the associated Ca 2ϩ currents raises the additional possibility that opioids might regulate vesicle fusion and/or trafficking independently of Ca 2ϩ current modulation. In any event, the present results suggest a potential mechanism whereby endogenous release of prodynorphin-derived opioid peptides, known to be colocalized in AVP-and OT-containing terminals (Zhao et al, 1988b;Russell et al, 1995), can exert inhibitory modulation of neuropeptide release from the neurohypophysis.…”

“…Opioids also depress neuropeptide release from the posterior pituitary, acting directly on vasopressin-(AVP) and oxytocin (OT)-containing neurons in the hypothalamus (Wuarin and Dudek, 1990;Renaud et al, 1992;Russell et al, 1995) and through presynaptic receptors located on their neurosecretory endings in the neurohypophysis (Zhao et al, 1988b;Kato et al, 1992). Although it remains unclear how the presynaptic inhibitory effects of opioids are manifested, measurements from neuronal somata suggest that the depression of release may result from reductions in Ca 2ϩ influx through voltage-dependent Ca 2ϩ channels (North, 1993).…”

Microarray Analysis Reveals Interleukin-6 as a Novel Secretory Product of the Hypothalamo-neurohypophyseal System

“…Following an osmotic challenge, dynorphin mRNA levels increase in the SON and the PVN (31-33), but dynorphin-like immunoreactivity in the posterior pituitary is reduced following prolonged salt-loading, suggesting peptide release (34). Dynorphin, co-released with VP, is probably a local modulator of neurosecretion in the neural lobe (35,36).…”

The Endomorphin System and Its Evolving Neurophysiological Role

“…The PVN and SON project to the posterior pituitary, where OT and AVP are secreted directly into the systemic circulation (Hatton, 1990). In vivo studies demonstrated that the opioid systems participate in regulation of the electrical activity of the OT and AVP neurons and the release of both hormones (Russell et al, 1995;Brown and Leng, 2000). The -opioid receptor agonists decreased the basal levels of both OT (Clarke et al, 1979;Frederickson et al, 1981;Clarke and Patrick, 1983;Hartman et al, 1987) and AVP (Van Wimersma Greidanus et al, 1979;Aziz et al, 1981).…”