Induction of thermal and mechanical hypersensitivity by parathyroid hormone–related peptide through upregulation of TRPV1 function and trafficking

Abstract

The neurobiological mechanisms underlying chronic pain associated with cancers are not well understood. It has been hypothesized that factors specifically elevated in the tumor microenvironment sensitize adjacent nociceptive afferents. We show that parathyroid hormone-related peptide (PTHrP), which is found at elevated levels in the tumor microenvironment of advanced breast and prostate cancers, is a critical modulator of sensory neurons. Intraplantar injection of PTHrP led to the development of thermal and mechanical hypersensitivity in both male and female mice, which were absent in mice lacking functional transient receptor potential vanilloid-1 (TRPV1). The PTHrP treatment of cultured mouse sensory neurons enhanced action potential firing, and increased TRPV1 activation, which was dependent on protein kinase C (PKC) activity. Parathyroid hormone-related peptide induced robust potentiation of TRPV1 activation and enhancement of neuronal firing at mild acidic pH that is relevant to acidic tumor microenvironment. We also observed an increase in plasma membrane TRPV1 protein levels after exposure to PTHrP, leading to upregulation in the proportion of TRPV1-responsive neurons, which was dependent on the activity of PKC and Src kinases. Furthermore, co-injection of PKC or Src inhibitors attenuated PTHrP-induced thermal but not mechanical hypersensitivity. Altogether, our results suggest that PTHrP and mild acidic conditions could induce constitutive pathological activation of sensory neurons through upregulation of TRPV1 function and trafficking, which could serve as a mechanism for peripheral sensitization of nociceptive afferents in the tumor microenvironment.

Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies

“…The nociceptive TRP channels are membrane proteins, and are localized to the neuronal/cell plasma membrane [84]. However, a significant fraction of channels, at least for TRPV1 and TRPA1 and TRPA1 have also been reported to be present in intracellular organelle membranes, which upon injury/inflammation undergo translocation to the plasma membrane [85,86,87,88]. Similar to the dearth of information on expression of other nociceptive TRP channels in the nervous system, their sub-cellular localization and modes of intracellular trafficking remain poorly understood.…”

“…These cellular signal transduction effectors induce post-translational modifications on multiple nociceptive channel proteins, leading to an increase in the activation of these channels (Figure 1), which results in an increase in nociceptor firing [9,11,13]. Specifically, modification of TRPV1 by protein kinases A and C (PKA & PKC), cyclin-dependent kinase-5 (Cdk5), Src kinase, and phosphoinositide kinases (PI3/4/5Ks) have all been shown to enhance activation of the channel by: (a) decreasing the temperature threshold of channel activation to physiological temperatures (~35 °C to 37 °C); (b) activating the channel at mildly/moderately acidic pH; and/or (c) enhancing plasma membrane delivery of the channel protein (Figure 1) [11,45,85,86,89,90,91,92,93,94,95,96,97]. Ca 2+ influx through TRPA1 and subsequent activation of PKA has also been shown to modulate TRPV1 channel function [98].…”

“…However, a large number of studies utilizing multiple animal models of inflammatory pain-like conditions have since suggested a critical role for TRPV1 in inflammatory mechanical hypersensitivity. These studies show attenuation of mechanical hypersensitivity by: (a) specific small molecule antagonists of TRPV1; and/or (b) administration of inflammatory mediators (or induction of inflammatory/disease conditions) in Trpv1 −/− mice [85,128,129,130,131,132,133,134]. In addition to TRPV1, TRPA1 has also been proposed to be involved in inflammatory mechanical hyperalgesia.…”

“…Specifically, studies have looked at cancer pain using rodent bone cancer models, and found that TRPV1 is critical for the development of cutaneous thermal and mechanical sensitivity, as well as paw guarding behavior [209,210]. There are many chemokines, cytokines and other factors that are released in the bone cancer microenvironment including prostaglandins, bradykinin, NGF, lysophosphatidic acid, and parathyroid hormone-related peptide, which have been shown to (or could presumably) sensitize TRPV1 currents leading to increased nociceptor firing [85,209,211,212,213]. Additionally, these mediators could potentially induce post-translational changes in TRPV1 and/or increase protein expression, which could lead to nociceptor sensitization.…”

Parathyroid Hormone-Related Protein and Prostate Cancer

“…Показано, что ПТГрП, присутствующий в по-вышенных количествах в микроокружении очагов рака предстательной железы, является критиче-ским фактором сенсибилизации смежных ноци-цептивных эфферентов, участвующих в реализа-ции механизмов хронической боли, связанной с онкологическим процессом [54].…”