Evidence Details for Mapk14
PMID Title Journal Year Abstract
31447579 Substance P modulates electroacupuncture analgesia in humanized mice with sickle cell disease. J Pain Res. 2019 Aug 1;12:2419-2426. doi: 10.2147/JPR.S210196. eCollection 2019. 2019 Purpose: Chronic pain is a major comorbidity of sickle cell disease (SCD). Acupuncture, a non-opioid and non-addictive therapy to treat pain, was found to reduce pain in the majority (80%) of SCD patients in an earlier retrospective review. We observed that electroacupuncture (EA) decreased hyperalgesia in transgenic mice with SCD with varied analgesia from high to moderate to no response. Interestingly, poor responders exhibited high levels of substance P (SP), a mediator of chronic pain, as well as active p38 MAPK in spinal cords. The present study aimed to investigate the roles of inhibition of SP and SP-activated p38 MAPK in chronic pain in sickle mice that are poorly responsive to EA intervention (moderate/non-responders). Materials and methods: Humanized mouse model with SCD defined as moderate- and non-responders to EA were intraperitoneally administered with antagonist of SP receptor NK1R (netupitant, 10 mg/kg/day, i.p.) or p38 MAPK inhibitor (SB203580, 10 mg/kg/day, i.p.) alone or in combination with EA (acupoint GB30, every 3rd day until day 12). Hyperalgesia to mechanical, thermal and cold stimuli, as well as deep tissue were measured. Phosphorylated p38 MAPK (phospho-p38 MAPK) in the lumbar spinal cord was quantified using western blotting. Phospho-p38 MAPK nuclear translocation in spinal dorsal horn was examined using immunohistochemical staining and confocal microscopy. Results: In EA poor-responders, combined treatment with EA and netupitant signi fi cantly enhanced the analgesic effects of EA in poor-responders on mechanical, heat, cold, and deep tissue pain, and decreased phosphorylation of p38 MAPK in lumbar spinal cords and its nuclear translocation in the spinal dorsal horn. Furthermore, combined treatment with EA and SB203580 significantly improved analgesic effects of EA on mechanical and heat hyperalgesia, but not cold or deep tissue hyperalgesia. However, additional EA treatment only, or administration of either netupitant or SB203580 alone did not lead to analgesic effects. Conclusions: These results suggest a pivotal role of SP in maintaining the chronic pain in SCD via spinal phospho-p38 MAPK signaling, which may hinder the effect of EA in poor responders. Inhibition of SP signaling pathway or activity of p38 MAPK significantly improved the EA analgesia In EA poor-responders with SCD, which provides a promising way to treat the chronic pain in patients with SCD."

Evidence Sentence: Phosphorylated p38 MAPK (phospho-p38 MAPK) in the lumbar spinal cord was quantified using western blotting.
Evidence Sentence: Phospho-p38 MAPK nuclear translocation in spinal dorsal horn was examined using immunohistochemical staining and confocal microscopy.
Evidence Sentence: Inhibition of SP signaling pathway or activity of p38 MAPK significantly improved the EA analgesia In EA poor-responders with SCD, which provides a promising way to treat the chronic pain in patients with SCD.
Evidence Sentence: Quantitative Western blot analysis of whole lumbar spinal cords showed that combined treatment with EA and netupitant in both moderate- and non-responders (Non/Moderate-responders + EA + Netupitant) significantly reduced the expression of phospho-p38 MAPK relative to total-p38 MAPK (Figure 3A, B).
Evidence Sentence: Nuclear co-localization of phospho-p38 MAPK in the dorsal horn of the spinal cord was highly insightful because nuclear translocation of p38 MAPK is critical in the transcriptional regulation of inflammatory cytokines.
Evidence Sentence: We observed a significantly high co-localization of phospho-p38 MAPK immunoreactivity in the nulei of non-responders (red and white dots indicated by yellow arrows in the cyan nuclei) compared to high- responders (Figure 3C, D).
Evidence Sentence: Similarly, moderate-responders also showed significantly higher nuclear presence of phospho-p38 MAPK compared to high-responders.
Evidence Sentence: Either netupitant or EA alone did not have any effect on nuclear phospho-p38 MAPK in non- or moderate-responders.
Evidence Sentence: Interestingly, poor responders exhibited high levels of substance P (SP), a mediator of chronic pain, as well as active p38 MAPK in spinal cords.
Evidence Sentence: The present study aimed to investigate the roles of inhibition of SP and SP-activated p38 MAPK in chronic pain in sickle mice that are poorly responsive to EA intervention (moderate/non-responders).
Evidence Sentence: or p38 MAPK inhibitor (SB203580, 10 mg/kg/day, i.p.)
Evidence Sentence: Phosphorylated p38 MAPK (phospho-p38 MAPK) in the lumbar spinal cord was quantified using western blotting.
Evidence Sentence: Results: In EA poor-responders, combined treatment with EA and netupitant significantly enhanced the analgesic effects of EA in poor-responders on mechanical, heat, cold, and deep tissue pain, and decreased phosphorylation of p38 MAPK in lumbar spinal cords and its nuclear translocation in the spinal dorsal horn.
Evidence Sentence: Quantitative Western blot analysis of whole lumbar spinal cords showed that combined treatment with EA and netupitant in both moderate- and non-responders (Non/Moderate-responders + EA + Netupitant) significantly reduced the expression of phospho-p38 MAPK relative to total-p38 MAPK (Figure 3A, B).
Evidence Sentence: Nuclear co-localization of phospho-p38 MAPK in the dorsal horn of the spinal cord was highly insightful because nuclear translocation of p38 MAPK is critical in the transcriptional regulation of inflammatory cytokines.
Evidence Sentence: However, combined treatment with EA and netupitant significantly inhibited p38 MAPK phosphorylation as well as its nuclear translocation.
Evidence Sentence: High-responders did not show significant p38 MAPK phosphorylation upon Western blotting (Figure 3A and B) or upon immunofluorescent co-localization in the cytoplasm and/or nuclear translocation (Figure 3C, D).
Evidence Sentence: Together these data suggest that the non-responsiveness to EA in non- and moderate-responders may be due to increased spinal p38 MAPK phosphorylation due to higher NK1R activity perhaps due to increased SP levels in these sickle mice.
Evidence Sentence: Conclusions: These results suggest a pivotal role of SP in maintaining the chronic pain in SCD via spinal phospho-p38 MAPK signaling, which may hinder the effect of EA in poor responders.