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Coexpressedδ-,μ-, andκ-Opioid Receptors Modulate Voltage-Gated Ca2+Channels in Gastric-Projecting Vagal Afferent Neurons

结节状神经节 类阿片 内分泌学 受体 内科学 化学 阿片受体 迷走神经 胃排空 刺激 医学
作者
Hannah J. Goudsward,Victor Ruiz‐Velasco,S Stella,Lisa B. Willing,Gregory M. Holmes
出处
期刊:Molecular Pharmacology [American Society for Pharmacology and Experimental Therapeutics]
卷期号:105 (3): 250-259 被引量:2
标识
DOI:10.1124/molpharm.123.000774
摘要

Opioid analgesics are frequently associated with gastrointestinal 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 CaV2.2 channels provide the majority (71% ± 16%) of Ca2+ currents in gastric vagal afferent neurons. Furthermore, we found that application of oxycodone, 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 that the nodose ganglia expresses low levels of δ-opioid receptors, we also determined the deltorphin II concentration-response relationship and assessed deltorphin-mediated Ca2+ current inhibition following exposure to the δ-opioid receptor antagonist ICI 174,864 (0.3 µM). The peak mean Ca2+ current inhibition following deltorphin II application was 47% ± 24% (EC50 = 302.6 nM), and exposure to ICI 174,864 blocked deltorphin II–mediated Ca2+ current inhibition (4% ± 4% versus 37% ± 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 (μ, δ, and κ) inhibit voltage-gated Ca2+ channels in a voltage-dependent mechanism by coupling to Gαi/o. These findings suggest that analgesics targeting any opioid receptor subtype would modulate gastric vagal circuits responsible for regulating gastric reflexes.
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