PMID- 36139848
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220928
IS  - 2076-3921 (Print)
IS  - 2076-3921 (Electronic)
IS  - 2076-3921 (Linking)
VI  - 11
IP  - 9
DP  - 2022 Sep 8
TI  - Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the 
      N-Methyl-d-Aspartate (NMDA) Receptors.
LID - 10.3390/antiox11091774 [doi]
LID - 1774
AB  - The management of post-operative (PO) pain has generally been shown to be 
      inadequate; therefore, acquiring a novel understanding of PO pain mechanisms 
      would increase the therapeutic options available. There is accumulating evidence 
      to implicate N-methyl-d-aspartate (NMDA) receptors in the induction and 
      maintenance of central sensitization during pain states by reinforcing glutamate 
      sensory transmission. It is known that DMF protects from oxidative glutamate 
      toxicity. Therefore, NMDA receptor antagonists have been implicated in 
      peri-operative pain management. Recent advances demonstrated that dimethyl 
      fumarate (DMF), a non-opioid and orally bioavailable drug, is able to resolve 
      neuroinflammation through mechanisms that drive nociceptive hypersensitivity. 
      Therefore, in this study, we evaluated the role of DMF on pain and 
      neuroinflammation in a mouse model of PO pain. An incision of the hind paw was 
      performed, and DMF at two different doses (30 and 100 mg/kg) was administered by 
      oral gavage for five consecutive days. Mechanical allodynia, thermal hyperalgesia 
      and locomotor dysfunction were evaluated daily for five days after surgery. Mice 
      were sacrificed at day 7 following PO pain induction, and hind paw and lumbar 
      spinal cord samples were collected for histological and molecular studies. DMF 
      administration significantly reduced hyperalgesia and allodynia, alleviating 
      motor disfunction. Treatment with DMF significantly reduced histological damage, 
      counteracted mast cell activation and reduced the nuclear factor 
      kappa-light-chain-enhancer of the activated B cell (NF-kappaB) inflammatory pathway, 
      in addition to downregulating tumor necrosis factor-alpha (TNF-alpha), Interleukin-1beta 
      (Il-1beta) and Il-4 expression. Interestingly, DMF treatment lowered the activation 
      of NMDA receptor subtypes (NR2B and NR1) and the NMDA-receptor-interacting PDZ 
      proteins, including PSD93 and PSD95. Furthermore, DMF interfered with calcium ion 
      release, modulating nociception. Thus, DMF administration modulated PO pain, 
      managing NMDA signaling pathways. The results suggest that DMF positively 
      modulated persistent nociception related to PO pain, through predominantly 
      NMDA-receptor-operated calcium channels.
FAU - Casili, Giovanna
AU  - Casili G
AD  - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, 
      University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166 Messina, 
      Italy.
FAU - Lanza, Marika
AU  - Lanza M
AD  - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, 
      University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166 Messina, 
      Italy.
FAU - Filippone, Alessia
AU  - Filippone A
AD  - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, 
      University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166 Messina, 
      Italy.
FAU - Cucinotta, Laura
AU  - Cucinotta L
AD  - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, 
      University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166 Messina, 
      Italy.
FAU - Paterniti, Irene
AU  - Paterniti I
AD  - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, 
      University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166 Messina, 
      Italy.
FAU - Repici, Alberto
AU  - Repici A
AD  - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, 
      University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166 Messina, 
      Italy.
FAU - Capra, Anna Paola
AU  - Capra AP
AUID- ORCID: 0000-0002-1428-3609
AD  - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, 
      University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166 Messina, 
      Italy.
FAU - Cuzzocrea, Salvatore
AU  - Cuzzocrea S
AUID- ORCID: 0000-0001-6131-3690
AD  - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, 
      University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166 Messina, 
      Italy.
FAU - Esposito, Emanuela
AU  - Esposito E
AUID- ORCID: 0000-0002-2663-6387
AD  - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, 
      University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166 Messina, 
      Italy.
FAU - Campolo, Michela
AU  - Campolo M
AD  - Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, 
      University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166 Messina, 
      Italy.
LA  - eng
PT  - Journal Article
DEP - 20220908
PL  - Switzerland
TA  - Antioxidants (Basel)
JT  - Antioxidants (Basel, Switzerland)
JID - 101668981
PMC - PMC9495385
OTO - NOTNLM
OT  - DMF
OT  - NMDA
OT  - calcium
OT  - post-operative pain (PO)
COIS- The authors declare no conflict of interest.
EDAT- 2022/09/24 06:00
MHDA- 2022/09/24 06:01
PMCR- 2022/09/08
CRDT- 2022/09/23 01:08
PHST- 2022/07/29 00:00 [received]
PHST- 2022/08/30 00:00 [revised]
PHST- 2022/09/06 00:00 [accepted]
PHST- 2022/09/23 01:08 [entrez]
PHST- 2022/09/24 06:00 [pubmed]
PHST- 2022/09/24 06:01 [medline]
PHST- 2022/09/08 00:00 [pmc-release]
AID - antiox11091774 [pii]
AID - antioxidants-11-01774 [pii]
AID - 10.3390/antiox11091774 [doi]
PST - epublish
SO  - Antioxidants (Basel). 2022 Sep 8;11(9):1774. doi: 10.3390/antiox11091774.