Melatonin MT2 receptor agonist IIK-7 produces antinociception by modulation of ROS and suppression of spinal microglial activation in neuropathic pain rats
Yaswanth Kuthati,1 Venkata Naga Goutham Davuluri,2 Chih-Ping Yang,3 Hsiao-Cheng Chang,1 Chih-Peng Chang,2 Chih Shung Wong1,41Department of Anesthesiology, Cathy General Hospital, Taipei, Taiwan; 2Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Ta...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2019-08-01
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| Series: | Journal of Pain Research |
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| Online Access: | https://www.dovepress.com/melatonin-mt2-receptor-agonist-iik-7-produces-antinociception-by-modul-peer-reviewed-article-JPR |
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| author | Kuthati Y Goutham Davuluri VN Yang CP Chang HC Chang CP Wong CS |
| author_facet | Kuthati Y Goutham Davuluri VN Yang CP Chang HC Chang CP Wong CS |
| author_sort | Kuthati Y |
| collection | DOAJ |
| description | Yaswanth Kuthati,1 Venkata Naga Goutham Davuluri,2 Chih-Ping Yang,3 Hsiao-Cheng Chang,1 Chih-Peng Chang,2 Chih Shung Wong1,41Department of Anesthesiology, Cathy General Hospital, Taipei, Taiwan; 2Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Anesthesiology, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan; 4Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, TaiwanBackground: In recent years, several melatonin (MLT) receptor agonists have been approved by FDA for the treatment of sleep disorders and depression. Very few studies have shed light on their efficacy against neuropathic pain (NP). IIK-7 is an MT-2 agonist known to promote sleep. Whether IIK-7 suppresses NP has not been reported, and the signaling profile is unknown.Objective: To investigate the effect of melatonin type 2 receptor agonist IIK-7 on partial sciatic nerve transection-induced NP in rats and elucidate the underlying molecular mechanisms.Methods: NP was induced by the PSNT in the left leg of adult male Wistar rats. On post-transection day 7, rats were implanted with intrathecal (i.t) catheter connected to an infusion pump and divided in to four groups: sham-operated/vehicle, PSNT/vehicle, PSNT/0.5 μg/hr IIK-7 and PSNT/0.5 μg IIK-7/1 μg 4-p/hr. To test the MT-2 dependence on IIK-7 activity, the animals were implanted with a single i.t catheter and injected MT-2 antagonist 4-Phenyl-2-propionamidotetralin (4-p) 20 mins prior to IIK-7 injection on day 7 after PSNT. The antinociceptive response was measured using a mechanical paw withdrawal threshold. Activation of microglial cells and the expression of NP-associated proteins in the spinal cord dorsal horn was assessed by immunofluorescence assay (IFA) and Western blotting (WB). Reactive oxygen species (ROS) scavenging ability of IIK-7 was evaluated by using bone marrow-derived macrophages (BMDM).Results: Treatment with the MT-2 agonist IIK-7 significantly alleviated PSNT-induced mechanical allodynia and glial activation along with the inhibition of P44/42 MAPK, HMGB-1, STAT3, iNOS and casp-3 proteins.Conclusion: IIK-7 attenuates NP through the suppression of glial activation and suppression of proteins involved in inflammation and apoptosis. MT-2 receptor agonists may establish a promising and unique therapeutic approach for the treatment of NP.Keywords: neuropathic pain, MT-2 receptor, IIK-7, allodynia |
| first_indexed | 2024-12-10T21:31:44Z |
| format | Article |
| id | doaj.art-e05b3b2988b44afbbd22890b5e137e81 |
| institution | Directory Open Access Journal |
| issn | 1178-7090 |
| language | English |
| last_indexed | 2024-12-10T21:31:44Z |
| publishDate | 2019-08-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Journal of Pain Research |
| spelling | doaj.art-e05b3b2988b44afbbd22890b5e137e812022-12-22T01:32:47ZengDove Medical PressJournal of Pain Research1178-70902019-08-01Volume 122473248547732Melatonin MT2 receptor agonist IIK-7 produces antinociception by modulation of ROS and suppression of spinal microglial activation in neuropathic pain ratsKuthati YGoutham Davuluri VNYang CPChang HCChang CPWong CSYaswanth Kuthati,1 Venkata Naga Goutham Davuluri,2 Chih-Ping Yang,3 Hsiao-Cheng Chang,1 Chih-Peng Chang,2 Chih Shung Wong1,41Department of Anesthesiology, Cathy General Hospital, Taipei, Taiwan; 2Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Anesthesiology, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan; 4Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, TaiwanBackground: In recent years, several melatonin (MLT) receptor agonists have been approved by FDA for the treatment of sleep disorders and depression. Very few studies have shed light on their efficacy against neuropathic pain (NP). IIK-7 is an MT-2 agonist known to promote sleep. Whether IIK-7 suppresses NP has not been reported, and the signaling profile is unknown.Objective: To investigate the effect of melatonin type 2 receptor agonist IIK-7 on partial sciatic nerve transection-induced NP in rats and elucidate the underlying molecular mechanisms.Methods: NP was induced by the PSNT in the left leg of adult male Wistar rats. On post-transection day 7, rats were implanted with intrathecal (i.t) catheter connected to an infusion pump and divided in to four groups: sham-operated/vehicle, PSNT/vehicle, PSNT/0.5 μg/hr IIK-7 and PSNT/0.5 μg IIK-7/1 μg 4-p/hr. To test the MT-2 dependence on IIK-7 activity, the animals were implanted with a single i.t catheter and injected MT-2 antagonist 4-Phenyl-2-propionamidotetralin (4-p) 20 mins prior to IIK-7 injection on day 7 after PSNT. The antinociceptive response was measured using a mechanical paw withdrawal threshold. Activation of microglial cells and the expression of NP-associated proteins in the spinal cord dorsal horn was assessed by immunofluorescence assay (IFA) and Western blotting (WB). Reactive oxygen species (ROS) scavenging ability of IIK-7 was evaluated by using bone marrow-derived macrophages (BMDM).Results: Treatment with the MT-2 agonist IIK-7 significantly alleviated PSNT-induced mechanical allodynia and glial activation along with the inhibition of P44/42 MAPK, HMGB-1, STAT3, iNOS and casp-3 proteins.Conclusion: IIK-7 attenuates NP through the suppression of glial activation and suppression of proteins involved in inflammation and apoptosis. MT-2 receptor agonists may establish a promising and unique therapeutic approach for the treatment of NP.Keywords: neuropathic pain, MT-2 receptor, IIK-7, allodyniahttps://www.dovepress.com/melatonin-mt2-receptor-agonist-iik-7-produces-antinociception-by-modul-peer-reviewed-article-JPRNeuropathic painMT-2 receptorIIK-7allodynia. |
| spellingShingle | Kuthati Y Goutham Davuluri VN Yang CP Chang HC Chang CP Wong CS Melatonin MT2 receptor agonist IIK-7 produces antinociception by modulation of ROS and suppression of spinal microglial activation in neuropathic pain rats Journal of Pain Research Neuropathic pain MT-2 receptor IIK-7 allodynia. |
| title | Melatonin MT2 receptor agonist IIK-7 produces antinociception by modulation of ROS and suppression of spinal microglial activation in neuropathic pain rats |
| title_full | Melatonin MT2 receptor agonist IIK-7 produces antinociception by modulation of ROS and suppression of spinal microglial activation in neuropathic pain rats |
| title_fullStr | Melatonin MT2 receptor agonist IIK-7 produces antinociception by modulation of ROS and suppression of spinal microglial activation in neuropathic pain rats |
| title_full_unstemmed | Melatonin MT2 receptor agonist IIK-7 produces antinociception by modulation of ROS and suppression of spinal microglial activation in neuropathic pain rats |
| title_short | Melatonin MT2 receptor agonist IIK-7 produces antinociception by modulation of ROS and suppression of spinal microglial activation in neuropathic pain rats |
| title_sort | melatonin mt2 receptor agonist iik 7 produces antinociception by modulation of ros and suppression of spinal microglial activation in neuropathic pain rats |
| topic | Neuropathic pain MT-2 receptor IIK-7 allodynia. |
| url | https://www.dovepress.com/melatonin-mt2-receptor-agonist-iik-7-produces-antinociception-by-modul-peer-reviewed-article-JPR |
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