TY - JOUR
T1 - A mast cell–specific receptor is critical for granuloma induced by intrathecal morphine infusion
AU - Zhang, Tao
AU - Liu, Rui
AU - Che, Delu
AU - Pundir, Priyanka
AU - Wang, Nan
AU - Han, Shengli
AU - Cao, Jiao
AU - Lv, Yanni
AU - Dong, Haiyan
AU - Fang, Fang
AU - Wang, Jue
AU - Ma, Pengyu
AU - Zhao, Tingting
AU - Lei, Ting
AU - Dong, Xinzhong
AU - He, Langchong
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (Grants 81230079 and 81227802).
Publisher Copyright:
Copyright © 2019 by The American Association of Immunologists, Inc.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Intrathecal morphine infusion is often applied to treat chronic pain related to cancer and other conditions. However, persistent pain can be caused by nerve compression because of granuloma formation. In this study, a mouse model of morphine-induced granuloma formation by intrathecal catheterization morphine infusion into the atlanto-occipital membrane of the foramen magnum was established in wild-type mice, MrgprB2 mutant (MrgprB22/2) mice, and in mast cell–deficient W-sash c-kit mutant (KitW-sh/W-sh) mice. Heat-related pain after surgery was performed to investigate the antipain effect of morphine. H&E staining and immunofluorescence staining of the spinal cord were applied to analyze the mechanism of granuloma formation. Morphine-induced mast cell degranulation was assessed by measuring the Ca2+ influx and mediator release. Anaphylactoid reactions were measured after s.c. morphine infusion to the paws. Chemokine release by mast cells was determined by Human XL Cytokine Array. Experiments with wild-type, MrgprB2 mutant, and mast cell–deficient W-sash c-kit mutant mice demonstrated that morphine activated mast cells and inflammatory cell aggregation through MrgprB2 in intrathecal infusion sites. The chemokine production of human mast cells demonstrated that granuloma formation is correlated with chemokines release. In addition, morphine activated mouse primary mast cells and de novo chemokine synthesis via the MRGPRX2 in human LAD2 cells. We concluded that granuloma formation during intrathecal morphine infusion was associated with MrgprB2/X2. Reducing MRGPRX2 potentially blocks morphine-induced side effects, including granuloma formation.
AB - Intrathecal morphine infusion is often applied to treat chronic pain related to cancer and other conditions. However, persistent pain can be caused by nerve compression because of granuloma formation. In this study, a mouse model of morphine-induced granuloma formation by intrathecal catheterization morphine infusion into the atlanto-occipital membrane of the foramen magnum was established in wild-type mice, MrgprB2 mutant (MrgprB22/2) mice, and in mast cell–deficient W-sash c-kit mutant (KitW-sh/W-sh) mice. Heat-related pain after surgery was performed to investigate the antipain effect of morphine. H&E staining and immunofluorescence staining of the spinal cord were applied to analyze the mechanism of granuloma formation. Morphine-induced mast cell degranulation was assessed by measuring the Ca2+ influx and mediator release. Anaphylactoid reactions were measured after s.c. morphine infusion to the paws. Chemokine release by mast cells was determined by Human XL Cytokine Array. Experiments with wild-type, MrgprB2 mutant, and mast cell–deficient W-sash c-kit mutant mice demonstrated that morphine activated mast cells and inflammatory cell aggregation through MrgprB2 in intrathecal infusion sites. The chemokine production of human mast cells demonstrated that granuloma formation is correlated with chemokines release. In addition, morphine activated mouse primary mast cells and de novo chemokine synthesis via the MRGPRX2 in human LAD2 cells. We concluded that granuloma formation during intrathecal morphine infusion was associated with MrgprB2/X2. Reducing MRGPRX2 potentially blocks morphine-induced side effects, including granuloma formation.
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U2 - 10.4049/jimmunol.1801423
DO - 10.4049/jimmunol.1801423
M3 - Article
C2 - 31484729
AN - SCOPUS:85072628256
SN - 0022-1767
VL - 203
SP - 1701
EP - 1714
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -