We hypothesized that TRPV4, a member of the transient receptor family of ion channels, functions as a sensory transducer for osmotic stimulus-induced nociception. We found that, as expected for a transducer molecule, TRPV4 protein is transported in sensory nerve distally toward the peripheral nerve endings. In vivo single-fiber recordings in rat showed that hypotonic solution activated 54% of C-fibers, an effect enhanced by the hyperalgesic inflammatory mediator prostaglandin E2. This osmotransduction causes nociception, since administration of a small osmotic stimulus into skin sensitized by PGE2 produced pain-related behavior. Antisense-induced decrease in expression of TRPV4 confirmed that the channel is required for hypotonic stimulus-induced nociception. Thus, we conclude that TRPV4 can function as an osmo-transducer in primary afferent nociceptive nerve fibers. Because this action is enhanced by an inflammatory mediator, TRPV4 may be important in pathological states and may be an attractive pharmacological target for the development of novel analgesics.

Patients with inflammatory or neuropathic pain experience hypersensitivity to mechanical, thermal and/or chemical stimuli. Given the diverse etiologies and molecular mechanisms of these pain syndromes, an approach to developing successful therapies may be to target ion channels that contribute to the detection of thermal, mechanical and chemical stimuli and promote the sensitization and activation of nociceptors. Transient Receptor Potential (TRP) channels have emerged as a family of evolutionarily conserved ligand-gated ion channels that contribute to the detection of physical stimuli. Six TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1) have been shown to be expressed in primary afferent nociceptors, pain sensing neurons, where they act as transducers for thermal, chemical and mechanical stimuli. This short review focuses on their contribution to pain hypersensitivity associated with peripheral inflammatory and neuropathic pain states.

The development of treatments for neuropathic pain has been hindered by our limited understanding of the basic mechanisms underlying abnormalities in nociceptor hyperexcitability. We recently showed that the polymodal receptor transient receptor potential vanilloid 4 (TRPV4), a member of the transient receptor potential (TRP) family of ion channels, may play a role in inflammatory pain (Alessandri-Haber et al., 2003). The present study tested whether TRVP4 also contributes to neuropathic pain, using a rat model of Taxol-induced painful peripheral neuropathy. Taxol is the most widely used drug for the treatment of a variety of tumor types, but the dose of Taxol that can be tolerated is limited by the development of a small-fiber painful peripheral neuropathy.We found that Taxol treatment enhanced the nociceptive behavioral responses to both mechanical and hypotonic stimulation of the hind paw. Spinal administration of antisense oligodeoxynucleotides to TRPV4, which reduced the expression of TRPV4 in sensory nerve, abolished Taxol-induced mechanical hyperalgesia and attenuated hypotonic hyperalgesia by 42%. The enhancement of osmotic nociception involves sensitization of osmotransduction in primary afferents because osmotransduction was enhanced in cultured sensory neurons isolated from Taxol-treated rats. Taxol-induced TRPV4-mediated hyperalgesia and the enhanced osmotransduction in cultured nociceptors were dependent on integrin/Src tyrosine kinase signaling. These results suggest that TRPV4 plays a crucial role in a painful peripheral neuropathy, making it a very promising target for the development of a novel class of analgesics.

Stress dramatically exacerbates pain in diseases such as fibromyalgia and rheumatoid arthritis, but the underlying mechanisms are unknown. We tested the hypothesis that stress causes generalized hyperalgesia by enhancing pronociceptive effects of immune mediators. Rats exposed to nonhabituating sound stress exhibited no change in mechanical nociceptive threshold, but showed a marked increase in hyperalgesia evoked by local injections of prostaglandin E 2 or epinephrine. This enhancement, which developed more than a week after exposure to stress, required concerted action of glucocorticoids and catecholamines at receptors located in the periphery on sensory afferents. The altered response to pronociceptive mediators involved a switch in coupling of their receptors from predominantly stimulatory to inhibitory G-proteins (G s to G i ), and for prostaglandin E 2 , emergence of novel dependence on protein kinase C. Thus, an important mechanism in generalized pain syndromes may be stress-induced coactivation of the hypothalamo-pituitary-adrenal and sympathoadrenal axes, causing a long-lasting alteration in intracellular signaling pathways, enabling normally innocuous levels of immune mediators to produce chronic hyperalgesia.

Although the transient receptor potential vanilloid 4 (TRPV4) has been implicated in the process of osmomechanical transduction, it appears to make little contribution to the normal somatosensory detection of mechanical stimuli. However, evidence suggests that it may play an important role in mechanical hyperalgesia. In the present study, we examined the common requirement for TRPV4 in mechanical hyperalgesia associated with diverse pain models and investigated whether the very close association observed between TRPV4 and mechanical hyperalgesia, regardless of etiology, reflects a close functional connection of TRPV4 with other molecules implicated in mechanical transduction. In models of painful peripheral neuropathy associated with vincristine chemotherapy, alcoholism, diabetes, and human immunodeficiency virus/acquired immune deficiency syndrome therapy, mechanical hyperalgesia was markedly reduced by spinal intrathecal administration of oligodeoxynucleotides antisense to TRPV4. Similarly, mechanical hyperalgesia induced by paclitaxel, vincristine, or diabetes was strongly reduced in TRPV4 knock-out mice. We also show that ␣2␤1 integrin and Src tyrosine kinase, which have been implicated in mechanical transduction, are important for the development of mechanical hyperalgesia, and that their contribution requires TRPV4. Furthermore, we establish a direct interaction between TRPV4, ␣2 integrin, and the Src tyrosine kinase Lyn in sensory neurons. We suggest that TRPV4 plays a role in mechanotransduction, as a component of a molecular complex that functions only in the setting of inflammation or nerve injury.