The neurobiological mechanisms underlying chronic pain in bone-metastasized breast and prostate cancer are not well understood although it is hypothesized that factors released in the tumor microenvironment may modulate sensory nociceptive sensory nerve fibers innervating the bone increasing pain sensation. Advanced metastatic breast and prostate cancer cells secrete high levels of parathyroid hormone-related peptide (PTHrP), which plays a critical role in metastasis to bones and subsequent tumor growth. PTHrP can activate parathyroid hormone receptor 1 (PTH1R), which signaling can activate either protein kinase C (PKC) and/or protein kinase A (PKA) depending on the tissue type. Both of these kinases are well known to modulate the nociceptive ion channel transient receptor potential vanilloid member 1 (TRPV1) due to which PTHrP constitutes an intriguing candidate that could modulate nociceptors, for pain sensitization related to cancer. TRPV1 can be activated by temperatures greater than 43°C and moderately acidic pH, less than pH 6. However, PKC and PKA phosphorylation of TRPV1 can potentiation channel activity by reducing the temperature of activation to 37°C and proton activation to pH 6.8 resulting in a channel that is constitutively active at body temperature or in the mildly acidic tumor microenvironment. Additionally, Src kinase, which under certain circumstances can be activated by PKC, can increase trafficking of TRPV1 to the plasma membrane, and enhance TRPV1-mediated signaling. Therefore, I hypothesize that PTHrP can sensitize TRPV1 and lead to an increase in nociceptive signaling. First I show that intraplantar PTHrP injection causes a TRPV1-dependent increase in thermal and mechanical hypersensitivity in mice. PTHrP treatment of cultured mouse dorsal root ganglion (DRG) neurons enhances TRPV1 activation and increases action potential firing, which was dependent on PKC activation. Furthermore, co-injection of PKC inhibitor attenuated PTHrP-induced thermal hypersensitivity. I also observed that PTHrP activated Src which led to an increase in the number of TRPV1-responsive neurons and an increase in TRPV1 protein level in the plasma membrane. While investigating the role of PTHrP-induced Src phosphorylation of TRPV1 I made a startling observation. Inhibition of Src phosphorylation of TRPV1 completely abolished PKC-induced potentiation of TRPV1. I found that Src phosphorylation of TRPV1 regulated PKC-induced potentiation of channel activity elicited by bradykinin, nerve growth factor and PMA. However, it did not regulate PKA induced potentiation of TRPV1 channel activity. In summary, my results suggest that PTHrP in the tumor microenvironment could induce constitutive pathological sensitization of adjacent nociceptive sensory fibers via upregulation of TRPV1 function, trafficking and expression. These actions are dependent on Src and PKC phosphorylation of TRPV1. Additionally, I found that Src regulates PKC-induced phosphorylation of TRPV1 by PTHrP as well as other inflammatory mediators, suggesting a crucial role for Src in PKC-induced sensitization of TRPV1.