Yong Fang Zhu1, Robert Ungard1, Eric Seidlitz1, Natalie Zacal1, Jan Huizinga2, James L Henry3, Gurmit Singh4. 1. Michael G. DeGroote Institute for Pain Research and Care, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. 2. Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. 3. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada. 4. Michael G. DeGroote Institute for Pain Research and Care, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada singhg@mcmaster.ca.
Abstract
BACKGROUND: Bone cancer pain is often severe, yet little is known about mechanisms generating this type of chronic pain. While previous studies have identified functional alterations in peripheral sensory neurons that correlate with bone tumours, none has provided direct evidence correlating behavioural nociceptive responses with properties of sensory neurons in an intact bone cancer model. RESULTS: In a rat model of prostate cancer-induced bone pain, we confirmed tactile hypersensitivity using the von Frey test. Subsequently, we recorded intracellularly from dorsal root ganglion neurons in vivo in anesthetized animals. Neurons remained connected to their peripheral receptive terminals and were classified on the basis of action potential properties, responses to dorsal root stimulation, and to mechanical stimulation of the respective peripheral receptive fields. Neurons included C-, Aδ-, and Aβ-fibre nociceptors, identified by their expression of substance P. We suggest that bone tumour may induce phenotypic changes in peripheral nociceptors and that these could contribute to bone cancer pain. CONCLUSIONS: This work represents a significant technical and conceptual advance in the study of peripheral nociceptor functions in the development of cancer-induced bone pain. This is the first study to report that changes in sensitivity and excitability of dorsal root ganglion primary afferents directly correspond to mechanical allodynia and hyperalgesia behaviours following prostate cancer cell injection into the femur of rats. Furthermore, our unique combination of techniques has allowed us to follow, in a single neuron, mechanical pain-related behaviours, electrophysiological changes in action potential properties, and dorsal root substance P expression. These data provide a more complete understanding of this unique pain state at the cellular level that may allow for future development of mechanism-based treatments for cancer-induced bone pain.
BACKGROUND:Bone cancer pain is often severe, yet little is known about mechanisms generating this type of chronic pain. While previous studies have identified functional alterations in peripheral sensory neurons that correlate with bone tumours, none has provided direct evidence correlating behavioural nociceptive responses with properties of sensory neurons in an intact bone cancer model. RESULTS: In a rat model of prostate cancer-induced bone pain, we confirmed tactile hypersensitivity using the von Frey test. Subsequently, we recorded intracellularly from dorsal root ganglion neurons in vivo in anesthetized animals. Neurons remained connected to their peripheral receptive terminals and were classified on the basis of action potential properties, responses to dorsal root stimulation, and to mechanical stimulation of the respective peripheral receptive fields. Neurons included C-, Aδ-, and Aβ-fibre nociceptors, identified by their expression of substance P. We suggest that bone tumour may induce phenotypic changes in peripheral nociceptors and that these could contribute to bone cancer pain. CONCLUSIONS: This work represents a significant technical and conceptual advance in the study of peripheral nociceptor functions in the development of cancer-induced bone pain. This is the first study to report that changes in sensitivity and excitability of dorsal root ganglion primary afferents directly correspond to mechanical allodynia and hyperalgesia behaviours following prostate cancer cell injection into the femur of rats. Furthermore, our unique combination of techniques has allowed us to follow, in a single neuron, mechanical pain-related behaviours, electrophysiological changes in action potential properties, and dorsal root substance P expression. These data provide a more complete understanding of this unique pain state at the cellular level that may allow for future development of mechanism-based treatments for cancer-induced bone pain.
Authors: Mary Ann C Sabino; Joseph R Ghilardi; Joost L M Jongen; Cathy P Keyser; Nancy M Luger; David B Mach; Christopher M Peters; Scott D Rogers; Matthew J Schwei; Carmen de Felipe; Patrick W Mantyh Journal: Cancer Res Date: 2002-12-15 Impact factor: 12.701
Authors: Yong Fang Zhu; Jacek M Kwiecien; Wojciech Dabrowski; Robert Ungard; Kan Lun Zhu; Jan D Huizinga; James L Henry; Gurmit Singh Journal: Mol Pain Date: 2018-10-16 Impact factor: 3.395
Authors: Robert G Ungard; Katja Linher-Melville; Mina G. Nashed; Manu Sharma; Jianping Wen; Gurmit Singh Journal: Mol Pain Date: 2019 Jan-Dec Impact factor: 3.395