Spinal Involvement of TRPV1 and PI3K/AKT/mTOR Pathway During Chronic Postoperative Pain in Mice

Overview

Journal Brain Sci

Publisher MDPI

Date 2025 Jan 24

PMID 39851421

Authors

Gabriela Xavier Santos

Tayllon Dos Anjos-Garcia

Ana Carolina de Jesus Vieira

Giovane Galdino

Affiliations

Soon will be listed here.

Abstract

Background: Chronic postoperative pain (CPOP) is among the main consequences of surgical procedures, directly affecting the quality of life. Although many strategies have been used to treat this symptom, they are often ineffective. Thus, studies investigating CPOP-associated mechanisms may help to develop more effective treatment strategies. Therefore, the present study investigated the spinal participation of the transient potential receptor vanilloid type 1 (TRPV1) and PI3K/AKT/mTOR pathway activation during CPOP.

Methods: In this study C57BL/6 male mice were used, and CPOP was induced by muscle retraction and incision. The nociceptive threshold was measured by the von Frey filament test. For pharmacological evaluation, TRPV1 and PI3K/AKT/mTOR inhibitors were administered intrathecally. TRPV1 and PI3K/AKT/mTOR protein levels were evaluated by Western blotting.

Results: The results showed that CPOP increased TRPV1 and mTOR protein levels, and pretreatment with the specific inhibitors alleviated CPOP. In addition, pretreatment with the TRPV1 antagonist SB-366791 attenuated mTOR protein levels.

Conclusions: The results suggest that TRPV1 and the PI3K/AKT/mTOR pathway are involved in CPOP at the spinal level, and TRPV1 may activate mTOR during this process.

References

Santos G, Barbosa D, de-Souza G, Kosour C, Parizotto N, Dos Reis L . Central involvement of 5-HT1A receptors in antinociception induced by photobiomodulation in animal model of neuropathic pain. Lasers Med Sci. 2021; 37(2):821-829. DOI: 10.1007/s10103-021-03318-w. View

Elisei L, Moraes T, Malta I, Charlie-Silva I, Sousa I, Veras F . Antinociception induced by artemisinin nanocapsule in a model of postoperative pain via spinal TLR4 inhibition. Inflammopharmacology. 2020; 28(6):1537-1551. DOI: 10.1007/s10787-020-00756-w. View

Jardin I, Lopez J, Diez R, Sanchez-Collado J, Cantonero C, Albarran L . TRPs in Pain Sensation. Front Physiol. 2017; 8:392. PMC: 5465271. DOI: 10.3389/fphys.2017.00392. View

Yoo S, Lim J, Hwang S . Sensory TRP channel interactions with endogenous lipids and their biological outcomes. Molecules. 2014; 19(4):4708-44. PMC: 6271031. DOI: 10.3390/molecules19044708. View

Dos Santos G, Delay L, Yaksh T, Corr M . Neuraxial Cytokines in Pain States. Front Immunol. 2020; 10:3061. PMC: 6997465. DOI: 10.3389/fimmu.2019.03061. View

Barabas M, Stucky C . TRPV1, but not TRPA1, in primary sensory neurons contributes to cutaneous incision-mediated hypersensitivity. Mol Pain. 2013; 9:9. PMC: 3602024. DOI: 10.1186/1744-8069-9-9. View

Gunthorpe M, Rami H, Jerman J, Smart D, Gill C, Soffin E . Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist. Neuropharmacology. 2003; 46(1):133-49. DOI: 10.1016/s0028-3908(03)00305-8. View

Liu Y, Liu Y, Jin H, Cong P, Zhang Y, Tong C . Cold stress-induced brain injury regulates TRPV1 channels and the PI3K/AKT signaling pathway. Brain Res. 2017; 1670:201-207. DOI: 10.1016/j.brainres.2017.06.025. View

Cui M, Gosu V, Basith S, Hong S, Choi S . Polymodal Transient Receptor Potential Vanilloid Type 1 Nocisensor: Structure, Modulators, and Therapeutic Applications. Adv Protein Chem Struct Biol. 2016; 104:81-125. DOI: 10.1016/bs.apcsb.2015.11.005. View

10.

Iftinca M, Defaye M, Altier C . TRPV1-Targeted Drugs in Development for Human Pain Conditions. Drugs. 2020; 81(1):7-27. DOI: 10.1007/s40265-020-01429-2. View

11.

Uchytilova E, Spicarova D, Palecek J . TRPV1 antagonist attenuates postoperative hypersensitivity by central and peripheral mechanisms. Mol Pain. 2014; 10:67. PMC: 4242597. DOI: 10.1186/1744-8069-10-67. View

12.

Cai S, Tee A, Short J, Bergeron J, Kim J, Shen J . Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. J Cell Biol. 2006; 173(2):279-89. PMC: 2063818. DOI: 10.1083/jcb.200507119. View

13.

Elokely K, Velisetty P, Delemotte L, Palovcak E, Klein M, Rohacs T . Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin. Proc Natl Acad Sci U S A. 2016; 113(2):E137-45. PMC: 4720335. DOI: 10.1073/pnas.1517288113. View

14.

Fuller A, Bharde S, Sikandar S . The mechanisms and management of persistent postsurgical pain. Front Pain Res (Lausanne). 2023; 4:1154597. PMC: 10357043. DOI: 10.3389/fpain.2023.1154597. View

15.

Szwed A, Kim E, Jacinto E . Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev. 2021; 101(3):1371-1426. PMC: 8424549. DOI: 10.1152/physrev.00026.2020. View

16.

Khan M, Khan A, Zafar S, Aslam S, Khan A, Shal B . Anti-nociceptive effects of magnolol via inhibition of TRPV1/P2Y and TLR4/NF-κB signaling in a postoperative pain model. Life Sci. 2022; 312:121202. DOI: 10.1016/j.lfs.2022.121202. View

17.

Yang J, Yu H, Zhou X, Kolosov V, Perelman J . Study on TRPV1-mediated mechanism for the hypersecretion of mucus in respiratory inflammation. Mol Immunol. 2012; 53(1-2):161-71. DOI: 10.1016/j.molimm.2012.06.015. View

18.

Palazzo E, Luongo L, de Novellis V, Berrino L, Rossi F, Maione S . Moving towards supraspinal TRPV1 receptors for chronic pain relief. Mol Pain. 2010; 6:66. PMC: 2959024. DOI: 10.1186/1744-8069-6-66. View

19.

Song C, Liu P, Zhao Q, Guo S, Wang G . TRPV1 channel contributes to remifentanil-induced postoperative hyperalgesia via regulation of NMDA receptor trafficking in dorsal root ganglion. J Pain Res. 2019; 12:667-677. PMC: 6388729. DOI: 10.2147/JPR.S186591. View

20.

Zhang W, Sun X, Bo J, Zhang J, Liu X, Wu L . Activation of mTOR in the spinal cord is required for pain hypersensitivity induced by chronic constriction injury in mice. Pharmacol Biochem Behav. 2013; 111:64-70. DOI: 10.1016/j.pbb.2013.07.017. View