Interaction with vesicle luminal protachykinin regulates surface expression of delta-opioid receptors and opioid analgesia.
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.
Guan
Ji-Song
JS
Institute of Neuroscience, Key Laboratory of Neurobiology, Chinese Academy of Sciences, Shanghai 200031, China.
Xu
Zhen-Zhong
ZZ
Gao
Hua
H
He
Shao-Qiu
SQ
Ma
Guo-Qiang
GQ
Sun
Tao
T
Wang
Li-Hua
LH
Zhang
Zhen-Ning
ZN
Lena
Isabelle
I
Kitchen
Ian
I
Elde
Robert
R
Zimmer
Andreas
A
He
Cheng
C
Pei
Gang
G
Bao
Lan
L
Zhang
Xu
X
D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D017353:Gene Deletion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D016716:PC12 Cells; D010146:Pain / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D011940:Receptor Aggregation / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D013373:Substance P / Q000737:chemistry / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015320:Tachykinins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D000701:Analgesics, Opioid; D011498:Protein Precursors; D011956:Receptors, Cell Surface; D017465:Receptors, Opioid, delta; D015320:Tachykinins; C054618:protachykinin; D013373:Substance P