Sensory neurons express a variety of temperature-sensing ion channels belonging to the TRP family, including the TRPV1 channel, which is normally activated only at noxious temperatures (e43oC). TRPV1 have been suggested to play a key role in the sensation of inflammatory and arthritic pain, as well as in pain associated with cancers. However, the precise molecular mechanisms underlying the initiation and maintenance of pain associated prostate cancer bone metastases are poorly understood. Here we propose a novel hypothesis on specific cross-talk between the metastatic prostate cancer cells in bone, as well as the tumor environment in the bone, and the adjacent sensory neurons. This cross-signaling is specifically mediated by distinct chemokine-induced sensitization and upregulation of TRPV1 activity and protein expression, which might underlie a mechanism of chronic pain associated with prostate cancer bone metastases. Our preliminary results show that two prominent chemokines, IL-8 and SDF-11, released at higher levels from bone- metastasized prostate cancer cells, as well as from the stromal/immune cells in the bone marrow, sensitize sensory neurons by enhancing TRPV1 channel activity in a phosphorylation-dependent manner, via activation of their respective receptors on sensory afferents. We also show that, sustained activation of these chemokine receptors in sensory neurons upregulate the expression of TRPV1 protein, and might decrease the temperature-activation threshold of the channel. As a result, these afferents can now be activated at below body temperatures, leading to constitutive nociceptor sensitization, a mechanism that could subserve chronic pain associated with prostate cancer bone metastases, experienced in the absence of any overt stimulation. We will utilize a scid mouse xenograft model of prostate cancer bone metastasis to quantitatively assay specific bone-related pain behaviors with gradual tumor growth/metastasis in bones.
Aim 1 will determine the role of bone metastasis/tumor growth specific chemokines on the upregulation of TRPV1 channel function and protein expression, and nociceptor sensitization.
Aim 2 will elucidate the specific intracellular signaling mechanisms underlying IL-8- and SDF-11-induced acute and sustained sensitization of TRPV1.
Aim 3 will determine the role of chemokine-mediated modulation of TRPV1 in sensory afferents on chronic pain sensitization in scid mice with xenografts of human prostate cancer cells that metastasize to bones. The proposed studies will advance our understanding of how the coordinated interplay between cancer cells, bone microenvironment and sensory neurons in metastatic bone cancers, initiates and sustains chronic pain sensitization. The results will suggest new therapies for pain associated with metastatic bone cancers.

Public Health Relevance

The TRPV1 protein has been suggested to play a key role in the sensation of inflammatory pain, as well as pain associated with cancers. Prostate cancer bone metastasis is associated with moderate to severe pain in the back, pelvis and hips. Although, therapeutic interventions focus mainly on pain relief in men suffering from prostate cancer bone metastasis, so as to improve the quality of their life, currently available analgesics often do not provide adequate pain relief, due to lack of specificity and unwanted side-effects. Understanding the precise molecular mechanisms by which prostate cancer metastasis and subsequent tumor growth in bones leads to acute and chronic pain, involving TRPV1 as the key transducer, could lead to the development of more efficient and more specific evidence-based pain therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Porter, Linda L
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University of Iowa
Schools of Medicine
Iowa City
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Shepherd, Andrew J; Mickle, Aaron D; Kadunganattil, Suraj et al. (2018) Parathyroid Hormone-Related Peptide Elicits Peripheral TRPV1-dependent Mechanical Hypersensitivity. Front Cell Neurosci 12:38
Shepherd, Andrew J; Copits, Bryan A; Mickle, Aaron D et al. (2018) Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain. J Neurosci 38:7032-7057
Shepherd, Andrew J; Mickle, Aaron D; Golden, Judith P et al. (2018) Macrophage angiotensin II type 2 receptor triggers neuropathic pain. Proc Natl Acad Sci U S A 115:E8057-E8066
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Meacham, Kathleen; Shepherd, Andrew; Mohapatra, Durga P et al. (2017) Neuropathic Pain: Central vs. Peripheral Mechanisms. Curr Pain Headache Rep 21:28
Rossi, Heather L; Broadhurst, Kimberly A; Luu, Anthony S K et al. (2016) Abnormal trigeminal sensory processing in obese mice. Pain 157:235-46
Mickle, Aaron D; Shepherd, Andrew J; Mohapatra, Durga P (2016) Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies. Pharmaceuticals (Basel) 9:
Shutov, Leonid P; Warwick, Charles A; Shi, Xiaoyu et al. (2016) The Complement System Component C5a Produces Thermal Hyperalgesia via Macrophage-to-Nociceptor Signaling That Requires NGF and TRPV1. J Neurosci 36:5055-70
Gupte, Raeesa P; Kadunganattil, Suraj; Shepherd, Andrew J et al. (2016) Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide. Neuropharmacology 101:291-308
Mickle, Aaron D; Shepherd, Andrew J; Mohapatra, Durga P (2015) Sensory TRP channels: the key transducers of nociception and pain. Prog Mol Biol Transl Sci 131:73-118

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