Transient Receptor Potential Vanilloid 4 Mediates Hypersensitivity in Chronic Sickle Cell Disease Pain

Sickle cell disease (SCD) pain is debilitating and severely diminishes patients’ quality of life. A significant cause of SCD pain is vaso-oclusion, however, pain in SCD can also arise from chronic tissue inflammation and neuropathy. Our lab is interested in identifying novel peripheral targets for treating chronic SCD pain. Transient receptor potential (TRP) channels are among these targets, as they have known somatosensory functions. One of these, TRPV4, is a nonselective cation channel involved in naïve somatosensation, as well as inflammatory and neuropathic pain. TRPV4 is expressed in dorsal root ganglia (DRG) neurons, the primary detectors and transducers of somatosensory information, and in keratinocytes, which compose the majority of the epidermis and are located proximal to afferent terminals in the skin. Further, inflammatory factors that interact with TRPV4, including neutrophil elastase and endothelin-1, are prevalent in SCD. Thus, TRPV4 is a likely contributor to SCD pain. In this study we investigated the role of TRPV4 in persistent SCD somatic hypersensitivity. First, we demonstrated that punctate mechanical allodynia observed in SCD mice was completely and dose-dependently blocked by a TRPV4 antagonist. Functional analysis of small-diameter DRG neurons (many of which are nociceptors in rodents) from SCD mice revealed a moderate TRPV4-mediated increase of calcium flux, and blocking TRPV4 receptors reduced the proportion of mechanically-sensitive neurons from SCD mice. In contrast to these modest DRG data, we found keratinocytes from SCD mice display robust TRPV4 agonist-induced calcium flux compared to WT controls. Given keratinocytes are profuse throughout the skin and are positioned alongside sensory nerve terminals, this evidence suggests keratinocytes play a pivotal role in TRPV4-mediated SCD hypersensitivity. Together, these data suggest TRPV4 plays an integral role in SCD evoked behavioral hypersensitivity, an effect that is likely due to sensitized TRPV4-mediated keratinocyte, and to a lesser extent DRG, activity in these mice. Grant support from R01 NS070711 NIH/NINDS.