The anti-inflammatory and analgesic effects of intraperitoneal melatonin after spinal nerve ligation are mediated by inhibition of the NF-κB/NLRP3 inflammasome signaling pathway.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
melatonin treatment | decrease | SNL-induced allodynia | rats | - | alleviated | #1 |
spinal nerve ligation (SNL) | increase | TNF-α, IL-18, IL-1β, NLRP3, ASC, cleaved caspase-1, and NF-κB | rats | - | induced upregulation | #2 |
intraperitoneal injection of melatonin | decrease | SNL-induced upregulation of TNF-α, IL-18, IL-1β, NLRP3, ASC, cleaved caspase-1, and NF-κB | rats | - | significantly attenuated | #3 |
intraperitoneal injection of VX-765 | decrease | SNL-induced upregulation of TNF-α, IL-18, IL-1β, NLRP3, ASC, cleaved caspase-1, and NF-κB | rats | - | significantly attenuated | #4 |
co-treatment of melatonin and 4P-PDOT | decrease | analgesic and anti-inflammatory effect of melatonin | rats | - | abrogated | #5 |
melatonin | decrease | SNL-induced neuropathic pain | rats | - | had potent analgesic and anti-inflammatory effects | #6 |
OBJECTIVE: To explore the potential analgesic effect of melatonin and its underlying molecular mechanisms in a neuropathic pain model induced by spinal nerve ligation (SNL). METHODS: The experimental animals were divided into different groups including sham, vehicle, melatonin (MT) treatment, caspase-1 inhibitor (VX-765) treatment and MT2 antagonist (4P-PDOT) treatment. On the first three successive postoperative days, rats were intraperitoneally administered with MT, VX-765 or combination of MT and 4P-PDOT. Hyperalgesic behavior after SNL was evaluated using the paw withdrawal threshold (PWT). We then assessed expression of tumor necrosis factor-α (TNF-α), IL-18, interleukin-1β (IL-1β), NLRP3 inflammasome components, and nuclear factor-κB (NF-κB) activation using enzyme-linked immunosorbent assay kits (ELISA), real-time PCR, immunohistochemistry, and western blot, respectively, in spinal cord horn tissues extracted on postoperative day 7. RESULTS: The results showed that melatonin treatment alleviated SNL-induced allodynia. We observed an SNL-induced upregulation of TNF-α, IL-18, IL-1β, NLRP3, ASC, cleaved caspase-1, and NF-κB in the lumbar spinal cord horn of rats, which was significantly attenuated by intraperitoneal injection of melatonin or VX-765. Additionally, co-treatment of melatonin and 4P-PDOT abrogated the analgesic and anti-inflammatory effect of melatonin. CONCLUSION: Melatonin had potent analgesic and anti-inflammatory effects in SNL-induced neuropathic pain via NF-κB/NLRP3 inflammasome signaling pathway. Our results therefore suggested that this pathway could represent a novel therapeutic target for the management of neuropathic pain.