TRPV4 Activation and its Intracellular Modulation Mediated by Kinin Receptors Contribute to Painful Symptoms Induced by Anastrozole

• Published in: Molecular neurobiology 2024-03, Vol.61 (3), p.1627-1642
• Main Authors: Fialho, Maria Fernanda Pessano, Brum, Evelyne Silva, Becker, Gabriela, Oliveira, Sara Marchesan
• Format: Article
• Language: English
• Subjects: Agonists; Anastrozole; Aromatase; Biomedical and Life Sciences; Biomedicine; Bradykinin; Cell Biology; Intracellular; Muscle strength; Neurobiology; Neurology; Neurosciences; Pain perception; Quality of life; Signal transduction; Therapeutic targets; Transient receptor potential proteins
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-023-03654-8

Anastrozole, an aromatase inhibitor, induces painful musculoskeletal symptoms, which affect patients’ quality of life and lead to therapy discontinuation. Efforts have been made to understand the mechanisms involved in these painful symptoms to manage them better. In this context, we explored the role of the Transient Receptor Potential Vanilloid 4 (TRPV4), a potential transducer of several nociceptive mechanisms, in anastrozole-induced musculoskeletal pain in mice. Besides, we evaluated the possible sensibilization of TRPV4 by signalling pathways downstream, PLC, PKC and PKCε from kinin B 2 (B 2 R) and B 1 (B 1 R) receptors activation in anastrozole-induced pain. Anastrozole caused mechanical allodynia and muscle strength loss in mice. HC067047, TRPV4 antagonist, reduced the anastrozole-induced mechanical allodynia and muscle strength loss. In animals previously treated with anastrozole, the local administration of sub-nociceptive doses of the TRPV4 (4α-PDD or hypotonic solution), B 2 R (Bradykinin) or B 1 R (DABk) agonists enhanced the anastrozole-induced pain behaviours. The sensitizing effects induced by local injection of the TRPV4, B 2 R and B 1 R agonists in animals previously treated with anastrozole were reduced by pre-treatment with TRPV4 antagonist. Furthermore, inhibition of PLC, PKC or PKCε attenuated the mechanical allodynia and muscle strength loss induced by TRPV4, B 2 R and B 1 R agonists. The generation of painful conditions caused by anastrozole depends on direct TRPV4 activation or indirect, e.g., PLC, PKC and PKCε pathways downstream from B 2 R and B 1 R activation. Thus, the TRPV4 channels act as sensors of extracellular and intracellular changes, making them potential therapeutic targets for alleviating pain related to aromatase inhibitors use, such as anastrozole.