Pregabalin inhibits purinergic P2Y2 receptor and TRPV4 to suppress astrocyte activation and to relieve neuropathic pain

Shasha Song; Qianwen Wang; Yujuan Qu; Wenshuang Gao; Danyang Li; Xiaoqian Xu; Shouwei Yue

doi:10.1016/j.ejphar.2023.176140

Pregabalin inhibits purinergic P2Y₂ receptor and TRPV4 to suppress astrocyte activation and to relieve neuropathic pain

Eur J Pharmacol. 2023 Dec 5:960:176140. doi: 10.1016/j.ejphar.2023.176140. Epub 2023 Nov 2.

Authors

Shasha Song¹, Qianwen Wang², Yujuan Qu¹, Wenshuang Gao¹, Danyang Li¹, Xiaoqian Xu¹, Shouwei Yue³

Affiliations

¹ Rehabilitation Center, Qilu Hospital of Shandong University, Jinan, Shandong, China.
² The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
³ Rehabilitation Center, Qilu Hospital of Shandong University, Jinan, Shandong, China. Electronic address: shouweiy@sdu.edu.cn.

PMID: 37925132
DOI: 10.1016/j.ejphar.2023.176140

Abstract

Backgrounds: Transient receptor potential vanilloid 4 (TRPV4)-mediated astrocyte activation is critical to neuropathic pain. Pregabalin, a widely used drug to treat chronic pain, is reported to lower the intracellular calcium level. However, the molecular mechanism by which pregabalin decreases the intracellular calcium level remains unknown. Purinergic P2Y₂ receptor-a member of the G protein-coupled receptor (GPCR) family-regulates calcium-related signal transduction in astrocyte activation. We investigated whether P2Y₂ receptor is involved in the pharmacological effects of pregabalin on neuropathic pain.

Methods: Neuropathic pain was induced by chronic compression of the dorsal root ganglion (CCD) in rats. Paw withdrawal mechanical threshold (PWMT) was used for behavioral testing. Intracellular calcium concentration was measured using a fluorescent calcium indicator (Fluo-4 AM).

Results: We found that P2Y₂ receptor protein was upregulated and astrocytes were activated in the experimental rats after CCD surgery. Lipopolysaccharide (LPS) increased the intracellular calcium concentration and induced astrocyte activation in cultured astrocytes but was prevented via P2Y₂ receptor inhibitor AR-C118925 or pregabalin. Furthermore, plasmid-mediated P2Y₂ receptor overexpression induced an elevation of the intracellular calcium levels and inflammation in astrocytes, which was abolished by the TRPV4 inhibitor HC-067047. AR-C118925, HC-067047, and pregabalin relieved neuropathic pain and inflammation in rats after CCD surgery. Finally, plasmid-mediated P2Y₂ receptor overexpression induced neuropathic pain in rats, which was abolished by pregabalin administration.

Conclusions: Pathophysiological variables that upregulated the P2Y₂ receptor/TRPV4/calcium axis contribute to astrocyte activation in neuropathic pain. Pregabalin exerts an analgesic effect by inhibiting this pathway.

Keywords: Astrocyte; Calcium; Neuropathic pain; Pregabalin; Purinergic P2Y(2) receptor; Transient receptor potential vanilloid 4.

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Astrocytes
Calcium / metabolism
Calcium Signaling
Inflammation / drug therapy
Neuralgia* / drug therapy
Neuralgia* / metabolism
Pregabalin / pharmacology
Pregabalin / therapeutic use
Rats
TRPV Cation Channels / metabolism

Substances

Pregabalin
AR-C118925
TRPV Cation Channels
Calcium
Antineoplastic Agents