A Transient Receptor Potential Vanilloid 4-Dependent Mechanism of Hyperalgesia Is Engaged by Concerted Action of Inflammatory Mediators

Abstract

The transient receptor potential vanilloid 4 (TRPV4) is a primary afferent transducer that plays a crucial role in neuropathic hyperalgesia for osmotic and mechanical stimuli, as well as in inflammatory mediator-induced hyperalgesia for osmotic stimuli. In view of the clinical importance of mechanical hyperalgesia in inflammatory states, the present study investigated the role of TRPV4 in mechanical hyperalgesia induced by inflammatory mediators and the second-messenger pathways involved. Intradermal injection of either the inflammogen carrageenan or a soup of inflammatory mediators enhanced the nocifensive paw-withdrawal reflex elicited by hypotonic or mechanical stimuli in rat. Spinal administration of TRPV4 antisense oligodeoxynucleotide blocked the enhancement without altering baseline nociceptive threshold. Similarly, in TRPV4 Ϫ/Ϫ knock-out mice, inflammatory soup failed to induce any significant mechanical or osmotic hyperalgesia. In vitro investigation showed that inflammatory mediators engage the TRPV4-mediated mechanism of sensitization by direct action on dissociated primary afferent neurons. Additional behavioral observations suggested that multiple mediators are necessary to achieve sufficient activation of the cAMP pathway to engage the TRPV4-dependent mechanism of hyperalgesia. In addition, direct activation of protein kinase A or protein kinase C ⑀, two pathways that mediate inflammation-induced mechanical hyperalgesia, also induced hyperalgesia for both hypotonic and mechanical stimuli that was decreased by TRPV4 antisense and absent in TRPV4 Ϫ/Ϫ mice. We conclude that TRPV4 plays a crucial role in the mechanical hyperalgesia that is generated by the concerted action of inflammatory mediators present in inflamed tissues.

Phosphatidylinositol-4,5-biphosphate-dependent rearrangement of TRPV4 cytosolic tails enables channel activation by physiological stimuli

“…structure | regulation | thermosensitivity T he transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel that responds to osmotic (1)(2)(3)(4), mechanical (5-7), and temperature stimulation (8), thereby contributing to many different physiological functions, including cellular (4,9) and systemic volume homeostasis (10), vasodilation (11,12), nociception (13), epithelial hydroelectrolyte transport (14), bladder voiding (15), ciliary beat frequency regulation (7,16,17), chondroprotection (18), and skeletal regulation (19). The osmotic (20) and mechanical (7,16) sensitivity of TRPV4 depends on the activation of phospholipase A 2 and subsequent production of the arachidonic acid metabolite 5′-6′-epoxyeicosatrienoic acid (EET), whereas the mechanism leading to temperature-mediated activation (observed only in intact cells) is not known at present (21).…”

TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells

“…As a result, 4␣-phorbol 12,13-didecanoate (4␣PDD) has become a valuable pharmacological tool to functionally test TRPV4 activity, because 4␣PDD interacts directly with transmembrane domains 3 and 4 of TRPV4 (17). TRPV4 can be also sensitized by coapplication of different stimuli (18)(19)(20) or participation of different cell signaling pathways (21). TRPV4 messenger and protein have been identified in both native ciliated epithelial cells of oviducts (21-23) and cell lines derived from human ciliated airway cells (24).…”

The Emerging Role of TRP Channels in Mechanisms of Temperature and Pain Sensation

“…Additional studies implicate TRPV4 channel in inflammatory and neuropathic pain [3][4][5][6]. TRPV4-/-mice show subtle impairment of osmotic regulation.…”