Abstract
Opioid and tachykinin systems are involved in modulation of pain transmission in the spinal cord. Regulation of surface opioid receptors on nociceptive afferents is critical for opioid analgesia. Plasma-membrane insertion of delta-opioid receptors (DORs) is induced by stimulus-triggered exocytosis of DOR-containing large dense-core vesicles (LDCVs), but how DORs become sorted into the regulated secretory pathway is unknown. Here we report that direct interaction between protachykinin and DOR is responsible for sorting of DORs into LDCVs, allowing stimulus-induced surface insertion of DORs and DOR-mediated spinal analgesia. This interaction is mediated by the substance P domain of protachykinin and the third luminal domain of DOR. Furthermore, deletion of the preprotachykinin A gene reduced stimulus-induced surface insertion of DORs and abolished DOR-mediated spinal analgesia and morphine tolerance. Thus, protachykinin is essential for modulation of the sensitivity of nociceptive afferents to opioids, and the opioid and tachykinin systems are directly linked by protachykinin/DOR interaction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Afferent Pathways / drug effects
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Afferent Pathways / metabolism
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Afferent Pathways / ultrastructure
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Analgesics, Opioid / pharmacology*
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Animals
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Cell Membrane / metabolism
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Cell Membrane / ultrastructure
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Cells, Cultured
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / metabolism
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Ganglia, Spinal / ultrastructure
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Gene Deletion
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Male
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Mice
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Mice, Knockout
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Microscopy, Electron, Transmission
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Neurons, Afferent / drug effects
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Neurons, Afferent / metabolism*
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Neurons, Afferent / ultrastructure
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Nociceptors / drug effects
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Nociceptors / metabolism*
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Nociceptors / ultrastructure
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PC12 Cells
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Pain / drug therapy
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Pain / metabolism
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Pain / physiopathology
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Protein Precursors / chemistry
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Protein Precursors / genetics
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Protein Precursors / metabolism*
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Protein Structure, Tertiary / physiology
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Rats
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Receptor Aggregation / physiology
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Receptors, Cell Surface / metabolism
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Receptors, Opioid, delta / metabolism*
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Secretory Vesicles / metabolism*
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Secretory Vesicles / ultrastructure
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Substance P / chemistry
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Substance P / metabolism
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology
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Tachykinins / chemistry
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Tachykinins / genetics
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Tachykinins / metabolism*
Substances
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Analgesics, Opioid
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Protein Precursors
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Receptors, Cell Surface
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Receptors, Opioid, delta
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Tachykinins
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protachykinin
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Substance P