Activation of Src Family Kinases in Spinal Microglia Contributes to Formalin-Induced Persistent Pain State Through p38 Pathway Yong-Hui Tan, Kai Li,

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Activation of Src Family Kinases in Spinal Microglia Contributes to Formalin-Induced Persistent Pain State Through p38 Pathway Yong-Hui Tan, Kai Li, Xin-Yi Chen, Ye Cao, Alan R. Light, Kai-Yuan Fu The Journal of Pain Volume 13, Issue 10, Pages 1008-1015 (October 2012) DOI: 10.1016/j.jpain.2012.07.010 Copyright © 2012 American Pain Society Terms and Conditions

Figure 1 Peripheral formalin injection induced SFK activation in the lumbar spinal dorsal horn. (A–C) Representative immunostaining images of p-SFKs expression in the spinal dorsal horn from naïve, saline- and formalin-injected groups at day 3 after injection. Scale bar: 50 μm. (D) p-SFK immunoreactivity increased in the ipsilateral side of the dorsal horn at day 3 after formalin injection. Scale bar: 100 μm. (E–G) Merged images of double immunofluorescent labels of p-SFKs (green) with markers of neurons (red, NeuN), astrocytes (red, GFAP), and microglia (red, OX-42). p-p38 was expressed in most microglia but rarely in neurons or astrocytes. Scale bars: 50 μm. The Journal of Pain 2012 13, 1008-1015DOI: (10.1016/j.jpain.2012.07.010) Copyright © 2012 American Pain Society Terms and Conditions

Figure 2 Representative bands and quantification of Western blot analysis showed persistent increased p-SFKs protein level in the lumbar spinal cord after formalin injection. Quantification of p-SFKs level were normalized against a control protein, β-actin. *P < .05, **P < .01, 1-way ANOVA and Tukey post hoc test, compared with the naïve (uninjected) control, n = 4. The Journal of Pain 2012 13, 1008-1015DOI: (10.1016/j.jpain.2012.07.010) Copyright © 2012 American Pain Society Terms and Conditions

Figure 3 Effects of the SFK inhibitor PP2 on formalin-induced early biphasic flinching behavior. (A) Time courses of flinching behavior number from 3 different treatment groups following peripheral 5% formalin injection. Each point was the mean number of flinches (±SEM) (n = 6) per 5-minute epoch. (B) The bars showed total numbers of flinches during the 2 phases in rats treated with vehicle, PP2, and PP3. No significance compared to vehicle group, n = 6, 1-way ANOVA, followed by a Tukey post hoc test. The Journal of Pain 2012 13, 1008-1015DOI: (10.1016/j.jpain.2012.07.010) Copyright © 2012 American Pain Society Terms and Conditions

Figure 4 Effects of the SFK inhibitor PP2 delivered intrathecally on formalin-evoked persistent hyperalgesia. (A) The mechanical hypersensitivity and percentage change from the baseline threshold were determined at days 1, 3, 5, and 7 after formalin injection, n = 6. (B) Western blot analysis reveals inhibition of SFK activation by PP2. Quantification of Western blot data is shown at right. **P < .01, ***P < .001 compared with the vehicle control, n = 4. The Journal of Pain 2012 13, 1008-1015DOI: (10.1016/j.jpain.2012.07.010) Copyright © 2012 American Pain Society Terms and Conditions

Figure 5 Effects of the SFK inhibitor PP2 delivered intrathecally on formalin-induced p38 MAPK activation in the dorsal horn. (A–C) p-p38 immunostaining in the dorsal horn in the vehicle, PP3, and PP2 groups at day 3 after formalin injection. Scale bar: 50 μm. (D) Western blot analysis indicated that PP2 suppressed the activation of p38 MAPK in the ipsilateral spinal cord at day 7. **P < .01 compared with the vehicle control, n = 4. The Journal of Pain 2012 13, 1008-1015DOI: (10.1016/j.jpain.2012.07.010) Copyright © 2012 American Pain Society Terms and Conditions