Co-expressed delta-, mu-, and kappa-opioid receptors modulate voltage-gated Ca 2+ channels in gastric-projecting vagal afferent neurons.

Opioid analgesics are frequently associated with gastrointestinal (GI) side effects including constipation, nausea, dysphagia, and reduced gastric motility. Though it has been shown that stimulation of opioid receptors expressed in enteric motor neurons contributes to opioid-induced constipation, it remains unclear whether activation of opioid receptors in gastric-projecting nodose ganglia neurons contributes to the reduction in gastric motility and emptying associated with opioid use. In the present study, whole-cell patch-clamp recordings were performed to determine the mechanism underlying opioid receptor-mediated modulation of Ca2+ currents in acutely isolated gastric vagal afferent neurons. Our results demonstrate that CaV 2.2 channels provide the majority (71 {plus minus} 16%) of Ca2+ currents in gastric vagal afferent neurons. Furthermore, we found that application of oxycodone, or U-50488, or deltorphin II on gastric nodose ganglia neurons inhibited Ca2+ currents through a voltage-dependent mechanism by coupling to the Gαi/o family of heterotrimeric G-proteins. Because previous studies have demonstrated the nodose ganglia expresses low levels of delta-opioid receptors, we also determined the deltorphin II concentration-response relationship and assessed deltorphin-mediated Ca2+ current inhibition following exposure to the delta-opioid receptor antagonist ICI 174, 864 (0.3 µM). The peak mean Ca2+ current inhibition following deltorphin II application was 47 {plus minus} 24% (EC50 =302.6 nM) and exposure to ICI 174,864 blocked deltorphin II-mediated Ca2+ current inhibition (4 {plus minus} 4% vs. 37 {plus minus} 20%). Together, our results suggest that analgesics targeting any opioid receptor subtype can modulate gastric vagal circuits. Significance Statement This study demonstrated that in gastric nodose ganglia neurons, agonists targeting all three classical opioid receptor subtypes (mu, delta, and kappa) inhibit voltage-gated Ca2+ channels in a voltage-dependent mechanism by coupling to Gαi/o These findings suggest analgesics targeting any opioid receptor subtype would modulate gastric vagal circuits responsible for regulating gastric reflexes.