Targeting TRPV4 Channels for Cancer Pain Relief

Simple Summary Cancer stands as a major public health concern worldwide, and a significant proportion of survivors are affected by recurrent and usually unrelieved cancer pain. The participation of ion channels in cancer pain's initiation and maintenance is well-described; however, the evidence on the contribution of transient receptor potential vanilloid 4 channels is scarce. The limited studies published to date encountered enhanced TRPV4 expression in cancer-induced bone pain (CIBP), perineural, and orofacial cancer models, increasing pain perception. These outcomes support the hypothesis that the modulation of TRPV4 channels can be targeted as a novel therapeutic approach for treating difficult pain. This review summarizes the role of TRPV4 in cancer etiology and cancer-induced pain mechanisms, as well as the current status of the clinical research.Abstract Despite the unique and complex nature of cancer pain, the activation of different ion channels can be related to the initiation and maintenance of pain. The transient receptor potential vanilloid 4 (TRPV4) is a cation channel broadly expressed in sensory afferent neurons. This channel is activated by multiple stimuli to mediate pain perception associated with inflammatory and neuropathic pain. Here, we focused on summarizing the role of TRPV4 in cancer etiology and cancer-induced pain mechanisms. Many studies revealed that the administration of a TRPV4 antagonist and TRPV4 knockdown diminishes nociception in chemotherapy-induced peripheral neuropathy (CIPN). Although the evidence on TRPV4 channels' involvement in cancer pain is scarce, the expression of these receptors was reportedly enhanced in cancer-induced bone pain (CIBP), perineural, and orofacial cancer models following the inoculation of tumor cells to the bone marrow cavity, sciatic nerve, and tongue, respectively. Effective pain management is a continuous problem for patients diagnosed with cancer, and current guidelines fail to address a mechanism-based treatment. Therefore, examining new molecules with potential antinociceptive properties targeting TRPV4 modulation would be interesting. Identifying such agents could lead to the development of treatment strategies with improved pain-relieving effects and fewer adverse effects than the currently available analgesics.