Background & Aims
Burn injury-induced pain (BIP) is a significant global health concern affecting various populations, including children, military veterans, and accident victims. Current treatments, primarily opioids, have inherent limitations such as addiction, respiratory depression, and sedation. We have dissected the role of phosphorylated focal adhesion kinase (p-FAK) in BIP and elucidated the complete underlying molecular mechanism.
Methods
In male SD rats, third-degree burn injury was performed using a soldering apparatus. Anti-pain effects of Defactinib (DFT), a potent p-FAK inhibitor were investigated using evoked and spontaneous ongoing pain behaviors. CNS-associated toxicity was also evaluated using Open field and rota-rod tests. finally, we have performed molecular analysis using RT-PCR and Western blotting.
Results
DFT significantly attenuated the evoked and spontaneous pain in burn-injured rats without any CNS-associated toxicity observed in the open field and rota rod test. Molecular analysis revealed that DFT treatment significantly attenuated the upregulation of NR2B in DRG of burn-injured rats by downregulating p-FAK and p-Erk1/2 pathways. Additionally, DFT reduced Substance P levels in the spinal cord while leaving CGRP unaffected. DFT also inhibited microglial activation and the release of multiple pro-inflammatory cytokines, restoring the levels of the anti-inflammatory cytokine IL-10 in the spinal cord.
Conclusions
The findings offer a thorough insight into the crucial role of p-FAK in regulating BIP and present encouraging prospects for the development of novel therapeutics for the treatment of burn injury-induced pain, effectively addressing the limitations associated with current treatments.
References
1.Alexis, A., Carrer, D., Pistiki, A., Louis, K., Droggiti, D., Meer, J. Van der, et al. (2012). Apoptosis of neutrophils, expression of TREM-1 on neutrophils and IL-17 responses in experimental burn in injury are related to the type and time of burn exposure. Crit. Care 16: 1–189.
2.Alomar, S.Y., Gheit, R.E.A. El, Enan, E.T., El-Bayoumi, K.S., Shoaeir, M.Z., Elkazaz, A.Y., et al. (2021). Novel mechanism for memantine in attenuating diabetic neuropathic pain in mice via downregulating the spinal HMGB1/TRL4/NF-kB inflammatory axis. Pharmaceuticals 14: 307.
3.Ashburn, M.A. (1995). Burn pain: the management of procedure-related pain. J. Burn Care Rehabil. 16: 365–371.
4.Brand, A., Smith, E.S.J., Lewin, G.R., and Park, T.J. (2010). Functional neurokinin and NMDA receptor activity in an animal naturally lacking substance P: the naked mole-rat. PLoS One 5: e15162.
5.Chen, C., Zhang, J., Sun, L., Zhang, Y., Gan, W.-B., Tang, P., et al. (2019). Long-term imaging of dorsal root ganglia in awake behaving mice. Nat. Commun. 10: 3087.
6.Coderre, T.J., and Melzack, R. (1991). Central neural mediators of secondary hyperalgesia following heat injury in rats: neuropeptides and excitatory amino acids. Neurosci. Lett. 131: 71–74.
7.Detloff, M.R., Fisher, L.C., McGaughy, V., Longbrake, E.E., Popovich, P.G., and Basso, D.M. (2008). Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats. Exp. Neurol. 212: 337–347.
8.Deuis, J.R., Dvorakova, L.S., and Vetter, I. (2017). Methods used to evaluate pain behaviors in rodents. Front. Mol. Neurosci. 10: 1–17.
9.Edelman, L.S. (2007). Social and economic factors associated with the risk of burn injury. Burns 33: 958–965.
10.Emery, M.A., and Eitan, S. (2020). Drug-specific differences in the ability of opioids to manage burn pain. Burns 46: 503–513.
11.Felice, M. De, Sanoja, R., Wang, R., Vera-Portocarrero, L., Oyarzo, J., King, T., et al. (2011). Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain. Pain 152: 2701–2709.
12.Fowler, M., Clifford, J.L., Garza, T.H., Slater, T.M., Arizpe, H.M., Novak, J., et al. (2014). A rat model of full thickness thermal injury characterized by thermal hyperalgesia, mechanical allodynia, pronociceptive peptide release and tramadol analgesia. Burns 40: 759–771.
13.Gadepalli, A., Ummadisetty, O., Chouhan, D., and Tiwari, V. (2023). Loperamide, a peripheral Mu-Opioid receptor agonist, attenuates chemotherapy-induced neuropathic pain in rats. Int. Immunopharmacol. 124: 110944.
14.Gupta, A., Keshri, G.K., Yadav, A., Gola, S., Chauhan, S., Salhan, A.K., et al. (2015). Superpulsed (Ga?As, 904 nm) low?level laser therapy (LLLT) attenuates inflammatory response and enhances healing of burn wounds. J. Biophotonics 8: 489–501.
15.Heng, M.C.Y. (2013). Signaling pathways targeted by curcumin in acute and chronic injury: Burns and photo?damaged skin. Int. J. Dermatol. 52: 531–543.
16.Hill, D.M., and DeBoer, E. (2023). State and Future Science of Opioids and Potential of Biased-ligand Technology in the Management of Acute Pain After Burn Injury. J. Burn Care Res. 44: 524–534.
17.Hulsebosch, C.E., Hains, B.C., Crown, E.D., and Carlton, S.M. (2009). Mechanisms of chronic central neuropathic pain after spinal cord injury. Brain Res. Rev. 60: 202–213.
18.Jeschke, M.G., Baar, M.E. van, Choudhry, M.A., Chung, K.K., Gibran, N.S., and Logsetty, S. (2020). Burn injury. Nat. Rev. Dis. Prim. 6: 11.
19.Jiang, X., Zhou, R., Zhang, Y., Zhu, T., Li, Q., and Zhang, W. (2022). Interleukin-17 as a potential therapeutic target for chronic pain. Front. Immunol. 13: 999407.
20.Jin, G.-L., He, S.-D., Lin, S.-M., Hong, L.-M., Chen, W.-Q., Xu, Y., et al. (2018). Koumine attenuates neuroglia activation and inflammatory response to neuropathic pain. Neural Plast. 2018:.
Presenting Author
Deepak Chouhan
Poster Authors
Topics
- Specific Pain Conditions/Pain in Specific Populations: Burn Pain