PMID- 37352811
OWN - NLM
STAT- MEDLINE
DCOM- 20230719
LR  - 20230719
IS  - 1879-1379 (Electronic)
IS  - 0022-3956 (Linking)
VI  - 164
DP  - 2023 Aug
TI  - PAG neuronal NMDARs activation mediated morphine-induced hyperalgesia by 
      HMGB1-TLR4 dependent microglial inflammation.
PG  - 150-161
LID - S0022-3956(23)00275-3 [pii]
LID - 10.1016/j.jpsychires.2023.05.082 [doi]
AB  - Morphine is one of the most effective and widely used analgesic drugs. However, 
      chronic morphine use caused opioid-induced hyperalgesia (OIH). The development of 
      OIH limits the use of morphine. The mechanisms of OIH are not fully understood. 
      Toll-like receptor4 (TLR4) and glutamate receptors in the periaqueductal gray 
      (PAG) are critical in OIH, however, the association between TLR4 and 
      N-methyl-D-aspartate Receptors (NMDARs) activation in PAG remains unclear. 
      Microglia activation, increased TLR4/p65 nuclear factor-kappa B (p65 NF-kappaB) and 
      proinflammatory cytokines in microglia, and phosphorylation of NMDAR1 subunit 
      (NR1) and NMDAR2B subunit (NR2B) in neurons were observed in PAG of OIH mice. 
      Up-regulations of TLR4/p65 NF-kappaB and proinflammatory cytokines (IL-1beta, IL-6, 
      TNF-alpha) in BV2 cells were prevented by inhibiting and knocking down TLR4. By 
      inhibiting myeloid differentiation factor 2 (MD2) and knocking down the 
      High-mobility group box 1 (HMGB1), we found that morphine activated TLR4 by HMGB1 
      but not MD2. We co-cultured Neuro-2a (N2A) with BV2 microglial cell line and 
      found that instead of directly phosphorylating NMDAR subunits, morphine increased 
      the phosphorylation of NR1 and NR2B by inducing TLR4-mediated microglia 
      inflammation. Knocking TLR4 out of PAG by Lentivirus-GFP-TLR4 shRNA reversed 
      these changes and relieved OIH. Our findings suggested that the secretion of 
      HMGB1 induced by morphine-activated TLR4 in microglia, and the proinflammatory 
      factors released by activated microglia phosphorylated NR1 and NR2B of adjacent 
      neurons, induced increased neuronal excitability. In conclusion, TLR4/NMDARs in 
      PAG were involved in the development and maintenance of OIH and supported novel 
      strategies for OIH treatment.
CI  - Copyright (c) 2023 Elsevier Ltd. All rights reserved.
FAU - Mo, Jingjing
AU  - Mo J
AD  - Department of Neurology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 
      Guangzhou, China.
FAU - Lu, Zijing
AU  - Lu Z
AD  - Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical 
      University, Guangzhou, 510510, Guangdong, China.
FAU - Peng, Jialing
AU  - Peng J
AD  - Department of Neurology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 
      Guangzhou, China; Department of Neurology, The Second Affiliated Hospital, 
      Guangzhou Medical University, Guangzhou, China.
FAU - Li, Xiang-Pen
AU  - Li XP
AD  - Department of Neurology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 
      Guangzhou, China.
FAU - Lan, Lihuan
AU  - Lan L
AD  - Department of Neurology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 
      Guangzhou, China.
FAU - Wang, Hongxuan
AU  - Wang H
AD  - Department of Neurology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 
      Guangzhou, China. Electronic address: wanghx8@mail.sysu.edu.cn.
FAU - Peng, Ying
AU  - Peng Y
AD  - Department of Neurology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 
      Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor 
      Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen 
      University, Guangzhou, 510828, Guangdong, China. Electronic address: 
      pengy2@mail.sysu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230615
PL  - England
TA  - J Psychiatr Res
JT  - Journal of psychiatric research
JID - 0376331
RN  - 76I7G6D29C (Morphine)
RN  - 0 (NF-kappa B)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (HMGB1 Protein)
RN  - 0 (Analgesics, Opioid)
RN  - 0 (Cytokines)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Morphine/adverse effects/metabolism
MH  - Hyperalgesia/chemically induced/metabolism
MH  - NF-kappa B/metabolism
MH  - Microglia/metabolism
MH  - Toll-Like Receptor 4/metabolism
MH  - Periaqueductal Gray/metabolism
MH  - Signal Transduction
MH  - *HMGB1 Protein/adverse effects/metabolism
MH  - Inflammation/chemically induced/metabolism
MH  - Analgesics, Opioid/adverse effects
MH  - Cytokines/metabolism
MH  - Neurons
OTO - NOTNLM
OT  - Microglial
OT  - NMDAR
OT  - OIH
OT  - PAG
OT  - TLR4
COIS- Declaration of competing interest The author(s) declared no potential conflicts 
      of interest with respect to the research, authorship, and/or publication of this 
      article.
EDAT- 2023/06/24 11:41
MHDA- 2023/07/19 06:43
CRDT- 2023/06/23 18:10
PHST- 2023/01/01 00:00 [received]
PHST- 2023/04/25 00:00 [revised]
PHST- 2023/05/30 00:00 [accepted]
PHST- 2023/07/19 06:43 [medline]
PHST- 2023/06/24 11:41 [pubmed]
PHST- 2023/06/23 18:10 [entrez]
AID - S0022-3956(23)00275-3 [pii]
AID - 10.1016/j.jpsychires.2023.05.082 [doi]
PST - ppublish
SO  - J Psychiatr Res. 2023 Aug;164:150-161. doi: 10.1016/j.jpsychires.2023.05.082. 
      Epub 2023 Jun 15.