PMID- 38147625
OWN - NLM
STAT- MEDLINE
DCOM- 20240313
LR  - 20240510
IS  - 1528-1175 (Electronic)
IS  - 0003-3022 (Linking)
VI  - 140
IP  - 4
DP  - 2024 Apr 1
TI  - Small G-Protein Rheb Gates Mammalian Target of Rapamycin Signaling to Regulate 
      Morphine Tolerance in Mice.
PG  - 786-802
LID - 10.1097/ALN.0000000000004885 [doi]
AB  - BACKGROUND: Analgesic tolerance due to long-term use of morphine remains a 
      challenge for pain management. Morphine acts on mu-opioid receptors and downstream 
      of the phosphatidylinositol 3-kinase signaling pathway to activate the mammalian 
      target of rapamycin (mTOR) pathway. Rheb is an important regulator of growth and 
      cell-cycle progression in the central nervous system owing to its critical role 
      in the activation of mTOR. The hypothesis was that signaling via the GTP-binding 
      protein Rheb in the dorsal horn of the spinal cord is involved in 
      morphine-induced tolerance. METHODS: Male and female wild-type C57BL/6J mice or 
      transgenic mice (6 to 8 weeks old) were injected intrathecally with saline or 
      morphine twice daily at 12-h intervals for 5 consecutive days to establish a 
      tolerance model. Analgesia was assessed 60 min later using the tail-flick assay. 
      After 5 days, the spine was harvested for Western blot or immunofluorescence 
      analysis. RESULTS: Chronic morphine administration resulted in the upregulation 
      of spinal Rheb by 4.27 +/- 0.195-fold (P = 0.0036, n = 6), in turn activating mTOR 
      by targeting rapamycin complex 1 (mTORC1). Genetic overexpression of Rheb 
      impaired morphine analgesia, resulting in a tail-flick latency of 4.65 +/- 1.10 s 
      (P < 0.0001, n = 7) in Rheb knock-in mice compared to 10 s in control mice 
      (10 +/- 0 s). Additionally, Rheb overexpression in spinal excitatory neurons led to 
      mTORC1 signaling overactivation. Genetic knockout of Rheb or inhibition of mTORC1 
      signaling by rapamycin potentiated morphine-induced tolerance (maximum possible 
      effect, 52.60 +/- 9.56% in the morphine + rapamycin group vs. 16.60 +/- 8.54% in the 
      morphine group; P < 0.0001). Moreover, activation of endogenous adenosine 
      5'-monophosphate-activated protein kinase inhibited Rheb upregulation and 
      retarded the development of morphine-dependent tolerance (maximum possible 
      effect, 39.51 +/- 7.40% in morphine + metformin group vs. 15.58 +/- 5.79% in morphine 
      group; P < 0.0001). CONCLUSIONS: This study suggests spinal Rheb as a key 
      molecular factor for regulating mammalian target of rapamycin signaling.
CI  - Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc., on 
      behalf of the American Society of Anesthesiologists.
FAU - Wang, Wenying
AU  - Wang W
AD  - Department of Anesthesiology, Sixth People's Hospital Affiliated with Shanghai 
      Jiao Tong University School of Medicine, Shanghai, China.
FAU - Ma, Xiaqing
AU  - Ma X
AD  - Department of Anesthesiology, Sixth People's Hospital Affiliated with Shanghai 
      Jiao Tong University School of Medicine, Shanghai, China.
FAU - Du, Wenjie
AU  - Du W
AD  - Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, 
      China.
FAU - Lin, Raozhou
AU  - Lin R
AD  - Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland.
FAU - Li, Zhongping
AU  - Li Z
AD  - Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland.
FAU - Jiang, Wei
AU  - Jiang W
AD  - Department of Anesthesiology, Sixth People's Hospital Affiliated with Shanghai 
      Jiao Tong University School of Medicine, Shanghai, China.
FAU - Wang, Lu-Yang
AU  - Wang LY
AD  - Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, 
      Ontario, Canada; and Department of Physiology, University of Toronto, Toronto, 
      Ontario, Canada.
FAU - Worley, Paul F
AU  - Worley PF
AD  - Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland.
FAU - Xu, Tao
AU  - Xu T
AUID- ORCID: 0000-0001-5868-4079
AD  - Department of Anesthesiology, Sixth People's Hospital Affiliated with Shanghai 
      Jiao Tong University School of Medicine, Shanghai, China; Department of 
      Anesthesiology, Suzhou Hospital of Anhui Medical University, Suzhou, China; and 
      Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Anesthesiology
JT  - Anesthesiology
JID - 1300217
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
RN  - 76I7G6D29C (Morphine)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
SB  - IM
EIN - Anesthesiology. 2024 May 10;:. PMID: 38728078
MH  - Female
MH  - Male
MH  - Mice
MH  - Animals
MH  - *Monomeric GTP-Binding Proteins/genetics/metabolism
MH  - Morphine/pharmacology
MH  - Sirolimus/pharmacology
MH  - Mice, Inbred C57BL
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Pain
MH  - Mammals/metabolism
EDAT- 2023/12/26 18:41
MHDA- 2024/03/13 06:46
CRDT- 2023/12/26 16:02
PHST- 2024/03/13 06:46 [medline]
PHST- 2023/12/26 18:41 [pubmed]
PHST- 2023/12/26 16:02 [entrez]
AID - 139605 [pii]
AID - 10.1097/ALN.0000000000004885 [doi]
PST - ppublish
SO  - Anesthesiology. 2024 Apr 1;140(4):786-802. doi: 10.1097/ALN.0000000000004885.