TY - JOUR
T1 - Parathyroid hormone-related peptide elicits peripheral TRPV1-dependent mechanical hypersensitivity
AU - Shepherd, Andrew J.
AU - Mickle, Aaron D.
AU - Kadunganattil, Suraj
AU - Hu, Hongzhen
AU - Mohapatra, Durga P.
N1 - Funding Information:
This work was supported by institutional T32 training grant NS045549 from the National Institute of General Medical Sciences (T32-NS045549), and NRSA pre-doctoral fellowship F31-CA171927 from the National Cancer Institute to ADM; from the National Institute of Neurological Disorders and Stroke (R01-NS069898), and US Department of Defense Prostate Cancer Research Program grant (PC101096) to DPM; and a Pilot and Feasibility award (to AJS) from a National Institute of Diabetes and Digestive and Kidney Diseases Center Core Grant (P30DK056341) awarded to the Nutrition and Obesity Research Center of Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Funding Information:
This work was supported by institutional T32 training grant NS045549 from the National Institute of General Medical Sciences (T32-NS045549), and NRSA pre-doctoral fellowship F31-CA171927 from the National Cancer Institute to ADM; from the National Institute of Neurological Disorders and Stroke (R01-NS069898), and US Department of Defense Prostate Cancer Research Program grant (PC101096) to DPM; and a Pilot and Feasibility award (to AJS) from a National Institute of Diabetes and Digestive and Kidney Diseases Center Core Grant (P30DK056341) awarded to the Nutrition and Obesity Research Center of Washington University School of Medicine in St. Louis, St. Louis, MO, USA.The authors would like to thank Ms. Sherri Vogt for help and assistance with animal breeding and handling, and Dr. Vaibhavkumar S. Gawali for performing a number of preliminary electrophysiological recordings on HEK293T cells.
Publisher Copyright:
© 2018 Shepherd, Mickle, Kadunganattil, Hu and Mohapatra.
PY - 2018/2/15
Y1 - 2018/2/15
N2 - Bone metastasis in breast, prostate and lung cancers often leads to chronic pain, which is poorly managed by existing analgesics. The neurobiological mechanisms that underlie chronic pain associated with bone-metastasized cancers are not well understood, but sensitization of peripheral nociceptors by tumor microenvironment factors has been demonstrated to be important. Parathyroid hormone-related peptide (PTHrP) is highly expressed in bone-metastasized breast and prostate cancers, and is critical to growth and proliferation of these tumors in the bone tumor microenvironment. Previous studies have suggested that PTHrP could sensitize nociceptive sensory neurons, resulting in peripheral pain hypersensitivity. In this study, we found that PTHrP induces both heat and mechanical hypersensitivity, that are dependent on the pain-transducing transient receptor potential channel family vanilloid, member-1 (TRPV1), but not the mechano-transducing TRPV4 and TRPA1 ion channels. Functional ratiometric Ca2+ imaging and voltage-clamp electrophysiological analysis of cultured mouse DRG neurons show significant potentiation of TRPV1, but not TRPA1 or TRPV4 channel activation by PTHrP. Interestingly, PTHrP exposure led to the slow and sustained activation of TRPV1, in the absence of any exogenous channel agonist, and is dependent on the expression of the type-1 parathyroid hormone receptor (PTH1), as well as on downstream phosphorylation of the channel by protein kinase C (PKC). Accordingly, local administration of specific small-molecule antagonists of TRPV1 to mouse hindpaws after the development of PTHrP-induced mechanical hypersensitivity led to its significant attenuation. Collectively, our findings suggest that PTHrP/PTH1-mediated flow activation of TRPV1 channel contributes at least in part to the development and maintenance of peripheral mechanical pain hypersensitivity, and could therefore constitute a mechanism for nociceptor sensitization in the context of metastatic bone cancer pain.
AB - Bone metastasis in breast, prostate and lung cancers often leads to chronic pain, which is poorly managed by existing analgesics. The neurobiological mechanisms that underlie chronic pain associated with bone-metastasized cancers are not well understood, but sensitization of peripheral nociceptors by tumor microenvironment factors has been demonstrated to be important. Parathyroid hormone-related peptide (PTHrP) is highly expressed in bone-metastasized breast and prostate cancers, and is critical to growth and proliferation of these tumors in the bone tumor microenvironment. Previous studies have suggested that PTHrP could sensitize nociceptive sensory neurons, resulting in peripheral pain hypersensitivity. In this study, we found that PTHrP induces both heat and mechanical hypersensitivity, that are dependent on the pain-transducing transient receptor potential channel family vanilloid, member-1 (TRPV1), but not the mechano-transducing TRPV4 and TRPA1 ion channels. Functional ratiometric Ca2+ imaging and voltage-clamp electrophysiological analysis of cultured mouse DRG neurons show significant potentiation of TRPV1, but not TRPA1 or TRPV4 channel activation by PTHrP. Interestingly, PTHrP exposure led to the slow and sustained activation of TRPV1, in the absence of any exogenous channel agonist, and is dependent on the expression of the type-1 parathyroid hormone receptor (PTH1), as well as on downstream phosphorylation of the channel by protein kinase C (PKC). Accordingly, local administration of specific small-molecule antagonists of TRPV1 to mouse hindpaws after the development of PTHrP-induced mechanical hypersensitivity led to its significant attenuation. Collectively, our findings suggest that PTHrP/PTH1-mediated flow activation of TRPV1 channel contributes at least in part to the development and maintenance of peripheral mechanical pain hypersensitivity, and could therefore constitute a mechanism for nociceptor sensitization in the context of metastatic bone cancer pain.
KW - Cancer pain
KW - Mechanical pain
KW - PTHrP
KW - Pain
KW - TRPA1
KW - TRPV1
KW - TRPV4
UR - http://www.scopus.com/inward/record.url?scp=85043586891&partnerID=8YFLogxK
U2 - 10.3389/fncel.2018.00038
DO - 10.3389/fncel.2018.00038
M3 - Article
C2 - 29497363
AN - SCOPUS:85043586891
VL - 12
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
SN - 1662-5102
M1 - 38
ER -