PMID- 29786105
OWN - NLM
STAT- MEDLINE
DCOM- 20181009
LR  - 20210223
IS  - 1791-244X (Electronic)
IS  - 1107-3756 (Print)
IS  - 1107-3756 (Linking)
VI  - 42
IP  - 2
DP  - 2018 Aug
TI  - Cannabinoid WIN-55,212-2 mesylate inhibits tumor necrosis factor-alpha-induced 
      expression of nitric oxide synthase in dorsal root ganglion neurons.
PG  - 919-925
LID - 10.3892/ijmm.2018.3687 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha) is an established pain modulator in the 
      peripheral nervous system. Elevated levels of TNF-alpha in dorsal root ganglion (DRG) 
      neurons reportedly is critical for neuropathic pain processing. It has been shown 
      that the production of nitric oxide, a key player in the development and 
      maintenance of nociception, depends on the expression of nitric oxide synthases 
      (NOSs) and their activities. Accumulating evidence also supports an important 
      role of cannabinoids in modulating neuropathic pain. In this study, we explored 
      the effects and the underlying mechanisms of crosstalk between TNF-alpha and 
      cannabinoid on the expression/activity of NOS in DRG neurons. With or without 
      knockdown of p38 mitogen-activated protein kinase (MAPK), DRG neurons were 
      treated with TNF-alpha in the presence or absence of synthetic cannabinoid 
      WIN-55,212-2 mesylate (WIN-55) and selective cannabinoid receptor (CB) 
      antagonists. TNF-alpha significantly increased the NOS activity as well as the mRNA 
      stability and expression of neuronal NOS (nNOS) in DRG neurons; this was 
      abolished by inhibiting p38 MAPK signaling. WIN-55 inhibited TNF-alpha-induced 
      p38 MAPK activity as well as TNF-alpha-induced increase of mRNA stability and 
      expression/activity of nNOS; the inhibitory effect of WIN-55 was blocked by a 
      selective CB2 antagonist. Our findings suggest that TNF-alpha induces the 
      expression/activity of nNOS in DRG neurons by increasing its mRNA stability by a 
      p38 MAPK-dependent mechanism; WIN-55 inhibits this effect of TNF-alpha by inhibiting 
      p38 MAPK via CB2. By linking the functions of TNF-alpha, NOS and cannabinoid in DRG 
      neurons, this study adds new insights into the molecular mechanisms underlying 
      the pharmacologic effects of cannabinoids on neuropathic pain as well as into the 
      pathophysiology of neuropathic pain.
FAU - Tan, Rong
AU  - Tan R
AD  - Department of Anesthesiology, The Second Xiangya Hospital, Central South 
      University, Changsha, Hunan 410011, P.R. China.
FAU - Cao, Lijun
AU  - Cao L
AD  - Department of Anesthesiology, The Second Xiangya Hospital, Central South 
      University, Changsha, Hunan 410011, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20180517
PL  - Greece
TA  - Int J Mol Med
JT  - International journal of molecular medicine
JID - 9810955
RN  - 0 (Analgesics)
RN  - 0 (Benzoxazines)
RN  - 0 (Cannabinoids)
RN  - 0 (Mesylates)
RN  - 0 (Morpholines)
RN  - 0 (Naphthalenes)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 5H31GI9502 
      ((3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
SB  - IM
MH  - Analgesics/*pharmacology
MH  - Animals
MH  - Benzoxazines/*pharmacology
MH  - Cannabinoids/*pharmacology
MH  - Cell Line
MH  - Ganglia, Spinal/cytology/*drug effects/metabolism
MH  - Gene Expression Regulation/*drug effects
MH  - Mesylates/pharmacology
MH  - Morpholines/*pharmacology
MH  - Naphthalenes/*pharmacology
MH  - Nitric Oxide Synthase/*genetics/metabolism
MH  - Rats
MH  - Tumor Necrosis Factor-alpha/*metabolism
PMC - PMC6034934
EDAT- 2018/05/23 06:00
MHDA- 2018/10/10 06:00
PMCR- 2018/05/17
CRDT- 2018/05/23 06:00
PHST- 2016/04/29 00:00 [received]
PHST- 2018/01/19 00:00 [accepted]
PHST- 2018/05/23 06:00 [pubmed]
PHST- 2018/10/10 06:00 [medline]
PHST- 2018/05/23 06:00 [entrez]
PHST- 2018/05/17 00:00 [pmc-release]
AID - ijmm-42-02-0919 [pii]
AID - 10.3892/ijmm.2018.3687 [doi]
PST - ppublish
SO  - Int J Mol Med. 2018 Aug;42(2):919-925. doi: 10.3892/ijmm.2018.3687. Epub 2018 May 
      17.