GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain
Neuropathic pain presents a significant challenge, with its underlying mechanisms still not fully understood. Here, we investigated the role of GluN2C- and GluN2D-containing NMDA receptors in the development of neuropathic pain induced by cisplatin, a widely used chemotherapeutic agent. Through gene...
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| Format: | Article |
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Elsevier
2025-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003863 |
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| author | Sukanya G. Gakare Gajanan P. Shelkar Dinesh Y. Gawande Ratnamala Pavuluri Pauravi J. Gandhi Shashank M. Dravid |
| author_facet | Sukanya G. Gakare Gajanan P. Shelkar Dinesh Y. Gawande Ratnamala Pavuluri Pauravi J. Gandhi Shashank M. Dravid |
| author_sort | Sukanya G. Gakare |
| collection | DOAJ |
| description | Neuropathic pain presents a significant challenge, with its underlying mechanisms still not fully understood. Here, we investigated the role of GluN2C- and GluN2D-containing NMDA receptors in the development of neuropathic pain induced by cisplatin, a widely used chemotherapeutic agent. Through genetic and pharmacological strategies, we found that GluN2D-containing NMDA receptors play a targeted role in regulating cisplatin-induced neuropathic pain (CINP), while sparing inflammatory or acute pain responses. Specifically, both GluN2D knockout (KO) mice and pharmacological blockade of GluN2D-containing receptors produced robust reduction in mechanical nocifensive response in CINP. In contrast, GluN2C KO mice behaved similar to wildtype mice in CINP but showed reduced mechanical hypersensitivity in inflammatory pain. Using conditional KO strategy, we addressed the region- and cell-type involved in GluN2D-mediated changes in CINP. Animals with conditional deletion of GluN2D receptors from parvalbumin interneurons (PVIs) or local ablation of GluN2D from nucleus accumbens (NAc) displayed reduced mechanical hypersensitivity in CINP, underscoring the pivotal role of accumbal GluN2D in PVIs in neuropathic pain. Furthermore, CINP increased excitatory neurotransmission in the NAc in wildtype mice and this effect is dampened in PV-GluN2D KO mice. Other changes in CINP in NAc included an increase in vGluT1 and c-fos labeled neurons in wildtype which were absent in PV-GluN2D KO mice. GiDREADD-induced inhibition of PVIs in the NAc produced reduction in mechanical hypersensitivity in CINP. These findings unveil a novel cell-type and region-specific role of GluN2D-containing NMDA receptors in neuropathic pain and identify PVIs in NAc as a novel mediator of pain behaviors. |
| format | Article |
| id | doaj-art-244c7c1284614c15ba2beaca9b610800 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-244c7c1284614c15ba2beaca9b6108002025-01-24T04:44:40ZengElsevierNeurobiology of Disease1095-953X2025-02-01205106784GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic painSukanya G. Gakare0Gajanan P. Shelkar1Dinesh Y. Gawande2Ratnamala Pavuluri3Pauravi J. Gandhi4Shashank M. Dravid5Department of Psychiatry and Behavioral Sciences, Texas A&M University School of Medicine, College Station, TX 77845, USADepartment of Psychiatry and Behavioral Sciences, Texas A&M University School of Medicine, College Station, TX 77845, USADepartment of Psychiatry and Behavioral Sciences, Texas A&M University School of Medicine, College Station, TX 77845, USADepartment of Psychiatry and Behavioral Sciences, Texas A&M University School of Medicine, College Station, TX 77845, USADepartment of Psychiatry and Behavioral Sciences, Texas A&M University School of Medicine, College Station, TX 77845, USACorresponding author.; Department of Psychiatry and Behavioral Sciences, Texas A&M University School of Medicine, College Station, TX 77845, USANeuropathic pain presents a significant challenge, with its underlying mechanisms still not fully understood. Here, we investigated the role of GluN2C- and GluN2D-containing NMDA receptors in the development of neuropathic pain induced by cisplatin, a widely used chemotherapeutic agent. Through genetic and pharmacological strategies, we found that GluN2D-containing NMDA receptors play a targeted role in regulating cisplatin-induced neuropathic pain (CINP), while sparing inflammatory or acute pain responses. Specifically, both GluN2D knockout (KO) mice and pharmacological blockade of GluN2D-containing receptors produced robust reduction in mechanical nocifensive response in CINP. In contrast, GluN2C KO mice behaved similar to wildtype mice in CINP but showed reduced mechanical hypersensitivity in inflammatory pain. Using conditional KO strategy, we addressed the region- and cell-type involved in GluN2D-mediated changes in CINP. Animals with conditional deletion of GluN2D receptors from parvalbumin interneurons (PVIs) or local ablation of GluN2D from nucleus accumbens (NAc) displayed reduced mechanical hypersensitivity in CINP, underscoring the pivotal role of accumbal GluN2D in PVIs in neuropathic pain. Furthermore, CINP increased excitatory neurotransmission in the NAc in wildtype mice and this effect is dampened in PV-GluN2D KO mice. Other changes in CINP in NAc included an increase in vGluT1 and c-fos labeled neurons in wildtype which were absent in PV-GluN2D KO mice. GiDREADD-induced inhibition of PVIs in the NAc produced reduction in mechanical hypersensitivity in CINP. These findings unveil a novel cell-type and region-specific role of GluN2D-containing NMDA receptors in neuropathic pain and identify PVIs in NAc as a novel mediator of pain behaviors.http://www.sciencedirect.com/science/article/pii/S0969996124003863GluN2DParvalbumin interneuronsNucleus accumbensCisplatin induced neuropathic pain |
| spellingShingle | Sukanya G. Gakare Gajanan P. Shelkar Dinesh Y. Gawande Ratnamala Pavuluri Pauravi J. Gandhi Shashank M. Dravid GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain Neurobiology of Disease GluN2D Parvalbumin interneurons Nucleus accumbens Cisplatin induced neuropathic pain |
| title | GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain |
| title_full | GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain |
| title_fullStr | GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain |
| title_full_unstemmed | GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain |
| title_short | GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain |
| title_sort | glun2d containing nmda receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain |
| topic | GluN2D Parvalbumin interneurons Nucleus accumbens Cisplatin induced neuropathic pain |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003863 |
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