Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate (NMDA) Receptors
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 <i>N</i>-methyl-<span style="font-v...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-09-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/11/9/1774 |
| _version_ | 1797491663647539200 |
|---|---|
| author | Giovanna Casili Marika Lanza Alessia Filippone Laura Cucinotta Irene Paterniti Alberto Repici Anna Paola Capra Salvatore Cuzzocrea Emanuela Esposito Michela Campolo |
| author_facet | Giovanna Casili Marika Lanza Alessia Filippone Laura Cucinotta Irene Paterniti Alberto Repici Anna Paola Capra Salvatore Cuzzocrea Emanuela Esposito Michela Campolo |
| author_sort | Giovanna Casili |
| collection | DOAJ |
| description | 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 <i>N</i>-methyl-<span style="font-variant: small-caps;">d</span>-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-κB) inflammatory pathway, in addition to downregulating tumor necrosis factor-α (TNF-α), Interleukin-1β (Il-1β) 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. |
| first_indexed | 2024-03-10T00:52:33Z |
| format | Article |
| id | doaj.art-19644efd33a0451098c977423167f843 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T00:52:33Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-19644efd33a0451098c977423167f8432023-11-23T14:48:41ZengMDPI AGAntioxidants2076-39212022-09-01119177410.3390/antiox11091774Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate (NMDA) ReceptorsGiovanna Casili0Marika Lanza1Alessia Filippone2Laura Cucinotta3Irene Paterniti4Alberto Repici5Anna Paola Capra6Salvatore Cuzzocrea7Emanuela Esposito8Michela Campolo9Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyThe 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 <i>N</i>-methyl-<span style="font-variant: small-caps;">d</span>-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-κB) inflammatory pathway, in addition to downregulating tumor necrosis factor-α (TNF-α), Interleukin-1β (Il-1β) 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.https://www.mdpi.com/2076-3921/11/9/1774post-operative pain (PO)DMFNMDAcalcium |
| spellingShingle | Giovanna Casili Marika Lanza Alessia Filippone Laura Cucinotta Irene Paterniti Alberto Repici Anna Paola Capra Salvatore Cuzzocrea Emanuela Esposito Michela Campolo Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate (NMDA) Receptors Antioxidants post-operative pain (PO) DMF NMDA calcium |
| title | Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate (NMDA) Receptors |
| title_full | Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate (NMDA) Receptors |
| title_fullStr | Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate (NMDA) Receptors |
| title_full_unstemmed | Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate (NMDA) Receptors |
| title_short | Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-Aspartate (NMDA) Receptors |
| title_sort | dimethyl fumarate dmf alleviated post operative po pain through the i n i methyl span style font variant small caps d span aspartate nmda receptors |
| topic | post-operative pain (PO) DMF NMDA calcium |
| url | https://www.mdpi.com/2076-3921/11/9/1774 |
| work_keys_str_mv | AT giovannacasili dimethylfumaratedmfalleviatedpostoperativepopainthroughtheinimethylspanstylefontvariantsmallcapsdspanaspartatenmdareceptors AT marikalanza dimethylfumaratedmfalleviatedpostoperativepopainthroughtheinimethylspanstylefontvariantsmallcapsdspanaspartatenmdareceptors AT alessiafilippone dimethylfumaratedmfalleviatedpostoperativepopainthroughtheinimethylspanstylefontvariantsmallcapsdspanaspartatenmdareceptors AT lauracucinotta dimethylfumaratedmfalleviatedpostoperativepopainthroughtheinimethylspanstylefontvariantsmallcapsdspanaspartatenmdareceptors AT irenepaterniti dimethylfumaratedmfalleviatedpostoperativepopainthroughtheinimethylspanstylefontvariantsmallcapsdspanaspartatenmdareceptors AT albertorepici dimethylfumaratedmfalleviatedpostoperativepopainthroughtheinimethylspanstylefontvariantsmallcapsdspanaspartatenmdareceptors AT annapaolacapra dimethylfumaratedmfalleviatedpostoperativepopainthroughtheinimethylspanstylefontvariantsmallcapsdspanaspartatenmdareceptors AT salvatorecuzzocrea dimethylfumaratedmfalleviatedpostoperativepopainthroughtheinimethylspanstylefontvariantsmallcapsdspanaspartatenmdareceptors AT emanuelaesposito dimethylfumaratedmfalleviatedpostoperativepopainthroughtheinimethylspanstylefontvariantsmallcapsdspanaspartatenmdareceptors AT michelacampolo dimethylfumaratedmfalleviatedpostoperativepopainthroughtheinimethylspanstylefontvariantsmallcapsdspanaspartatenmdareceptors |