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

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 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 PLCγ, which promotes cleavage of the inhibitory PIP2 from the channel. In turn, PLCγ is activated via its phosphorylation by growth factor receptor tyrosine kinases, such as the high affinity nerve growth factor receptor, TrkA. We previously developed a permeable phosphopeptide (TAT-pQYP) that binds to PLCγ, preventing lipase anchoring to TrkA, and hence its phosphorylation/activation, and showed that PLCγ is key for mechanical hypersensitivity in CFA-induced inflammation. Herewith, we investigate the role of PLCγ 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 PLCγ signaling, reverting NGF/TrkA-dependent mechanical hypersensitivity in nociceptors, and returning paw diameter to baseline levels by disrupting VEGFA/eNOS signaling in endothelial cells. Altogether, our results show that TAT-pQYP disrupts PLCγ signaling in CAP-triggered neurogenic inflammation, leading to an anti-inflammatory and anti-nociceptive effect without interfering with TRPV1 chemosensitivity and neuropeptides activity. PLCγ represents a potential target to relieve neurogenic inflammation-dependent pain while preserving TRPV1's physiological activity.