Differential Effects of μ-Opioid Receptor Ligands on Ca²⁺Signaling

Abstract

Activation of -opioid receptors (MORs) transfected into human embryonic kidney 293 cells, caused a multiphasic increase in cytosolic free Ca 2ϩ levels (Ca 2ϩ i). The first Ca 2ϩ i maximum (peak 1) between 5 and 7 s depended on the presence of extracellular Ca 2ϩ (Ca 2ϩ e). The second phase peaking at ϳ15 s (peak 2) was independent of Ca 2ϩ e and thus represents Ca 2ϩ release from intracellular stores. A decrease in temperature from 37 to 25°C also caused reduction of peak 1 but not peak 2, suggesting that the two responses arise from mechanistically distinct pathways. A delayed Ca 2ϩ e-dependent third response phase is thought to represent capacitative Ca 2ϩ e influx evoked after release of Ca 2ϩ from internal stores. Agonists and antagonists of two major classes of opioid ligands, oxymorphinans (morphine and naloxone) and oripavines (etorphine and diprenorphine), had differential effects on Ca 2ϩ currents. Although morphine activated both phases with equal potency, etorphine was 20-fold less potent at stimulating peak 1 over peak 2.

Differential Effects of CB1 and Opioid Agonists on Two Populations of Adult Rat Dorsal Root Ganglion Neurons

“…CP 55,940 and morphine did not modulate basal [Ca 2ϩ ] i . Increases in [Ca 2ϩ ] i in response to high concentrations of opioid agonists have been described in cultured embryonic mouse DRG neurons (Tang et al, 1996) and cells transfected with a cloned MOR (Quillan et al, 2002). It is not likely that our protocol masked an effect of opioids on basal [Ca 2ϩ ] i .…”

Chronic Morphine Treatment Promotes Specific Th2 Cytokine Production by Murine T Cells In Vitro via a Fas/Fas Ligand-Dependent Mechanism

“…It is known that the expression of Fas requires protein kinase C (PKC) and expression of FasL requires both PKC and cytosolic Ca 2ϩ (28). Because signaling through the MOR enhances cytosolic free Ca 2ϩ levels in human embryonic kidney 293 cells (29,30) and also induces PKC activation in the rat brain (31), it is possible that activation of PKC and cytosolic Ca 2ϩ release by morphine may lead to enhanced Fas and FasL expression during TCR activation. Interestingly, resting splenic T cells have also been shown to express ␦ opioid receptor (DOR) mRNA transcripts whose expression can be enhanced or inhibited depending upon the use of anti-CD3 or PMA and ionomycin, respectively, to stimulate T cells (32,33).…”

Reversal of Morphine Antinociceptive Tolerance and Dependence by the Acute Supraspinal Inhibition of Ca2+/Calmodulin-Dependent Protein Kinase II

“…On the other hand, intracellular Ca 2ϩ , calmodulin, and CaMKII can all be regulated by opioids. Cytosolic free Ca 2ϩ was increased after the treatment with opioids (Fields and Sarne, 1997;Smart et al, 1997;Spencer et al, 1997;Quillan et al, 2002). Likewise, chronic treatments with opioids have been found to increase calmodulin activity (Nehmad et al, 1982) and mRNA levels (Niu et al, 2000).…”