PLCγ has a dual role in capsaicin-triggered neurogenic inflammation promoting mechanical hypersensitivity and edema in male mice

Author(s)

do Nascimento, Alexandre M. ; Rodrigues, Ana M. ; Ramos, Heloisa E. G. ; de Moraes, Beatriz C. ; Santos, Raphael S. ; Dale, Camila S. ; Schechtman, Deborah

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY; v. 329, n. 3, p. 13-pg., 2025-09-11.

Abstract

Understanding the signaling mechanisms leading to neurogenic inflammation, a process found in chronic pain, psoriasis and migraine, is key for the development of more effective analgesics. A key player in the onset of this inflammation is transient receptor potential cation channel, subfamily V, member 1 (TRPV1), an ion channel abundant at the free terminals of nociceptors, which can be directly activated by capsaicin (CAP), acidic pH or noxious heat, and indirectly through phospholipase C-gamma (PLC gamma), which promotes cleavage of the inhibitory phosphatidylinositol-4,5-bisphosphate from the channel. In turn, PLC gamma is activated via its phosphorylation by growth factor receptor tyrosine kinases, such as the high affinity nerve growth factor receptor, tropomyosin kinase A (TrkA). We previously developed a permeable phosphopeptide (TAT-pQYP) that binds to PLC gamma, preventing lipase anchoring to TrkA, and hence its phosphorylation/activation, and showed that PLC gamma is key for mechanical hypersensitivity in CFA-induced inflammation. Herewith, we investigate the role of PLC gamma in an acute model of inflammatory nociception induced by the subcutaneous injection of CAP in the hind paw of male mice. This model elicited a two phase response, the first related to TRPV1's sensitization and the latter to neurogenic inflammation. TAT-pQYP did not alter the TRPV1-mediated chemonociceptive response and neurogenic signaling itself, but it was able to disrupt PLC gamma signaling, reverting nerve growth factor/TrkA-dependent mechanical hypersensitivity in nociceptors, and returning paw diameter to baseline levels by disrupting vascular endothelial growth factor A/endothelial nitric oxide synthase signaling in endothelial cells. Altogether, our results show that TAT-pQYP disrupts PLC gamma signaling in CAP-triggered neurogenic inflammation, leading to an anti-inflammatory and antinociceptive effect without interfering with TRPV1 chemosensitivity and neuropeptides activity. PLC gamma represents a potential target to relieve neurogenic inflammation-dependent pain while preserving TRPV1's physiological activity. <bold>NEW & NOTEWORTHY</bold> When activated, TRPV1 promotes neurogenic inflammation via neuropeptide signaling. However, drugs designed to directly block TRPV1 may impair its nociceptive roles, essential for tissue preservation. In this work, pain and swelling caused by neurogenic inflammation were mitigated after blocking PLC gamma's activity, modulating TRPV1's activity without affecting normal chemosensitivity. This suggests that blocking PLC gamma could be a new approach for the development of painkillers maintaining the physiological detection of harmful stimuli. (AU)

• FAPESP's process: 22/00594-7 - Role of PLCg in experimental acute and chronic hypersensitivity
• Grantee: Beatriz Caroline de Moraes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 23/09168-3 - Identification of TAT-pQYP peptide ligands
• Grantee: Heloisa Espreafico Guelerman Ramos
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 19/06982-6 - Characterization and development of new modulators of the TrkA and PKMzeta pathways in inflammatory and chronic pain
• Grantee: Deborah Schechtman
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 23/10572-3 - Implementing assays for the screening of new drugs (small molecules and peptides) that have TrkA as a target.
• Grantee: Ana Maria Rodrigues Henrique
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 24/20449-7 - Study of the effect of pQYP and QEP peptides on protein interactions and signaling pathways in the dorsal root ganglion of mice.
• Grantee: Raphael Lobato de Siqueira Santos
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training