Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain

Christopher M. Peters, Joseph R. Ghilardi, Cathy P. Keyser, Kazufumi Kubota, Theodore H. Lindsay, Nancy M. Luger, David B. Mach, Matthew J. Schwei, Molly A. Sevcik, Patrick W Mantyh

Research output: Contribution to journalArticle

143 Citations (Scopus)

Abstract

Bone is the most common site of chronic pain in patients with metastatic cancer. What remains unclear are the mechanisms that generate this pain and why bone cancer pain can be so severe and refractory to treatment with opioids. Here we show that following injection and confinement of NCTC 2472 osteolytic tumor cells within the mouse femur, tumor cells sensitize and injure the unmyelinated and myelinated sensory fibers that innervate the marrow and mineralized bone. This tumor-induced injury of sensory nerve fibers is accompanied by an increase in ongoing and movement-evoked pain behaviors, an upregulation of activating transcription factor 3 (ATF3) and galanin by sensory neurons that innervate the tumor-bearing femur, upregulation of glial fibrillary acidic protein (GFAP) and hypertrophy of satellite cells surrounding sensory neuron cell bodies within the ipsilateral dorsal root ganglia (DRG), and macrophage infiltration of the DRG ipsilateral to the tumor-bearing femur. Similar neurochemical changes have been described following peripheral nerve injury and in other non-cancerous neuropathic pain states. Chronic treatment with gabapentin did not influence tumor growth, tumor-induced bone destruction or the tumor-induced neurochemical reorganization that occurs in sensory neurons or the spinal cord, but it did attenuate both ongoing and movement-evoked bone cancer-related pain behaviors. These results suggest that even when the tumor is confined within the bone, a component of bone cancer pain is due to tumor-induced injury to primary afferent nerve fibers that innervate the tumor-bearing bone. Tumor-derived, inflammatory, and neuropathic mechanisms may therefore be simultaneously driving this chronic pain state.

Original languageEnglish (US)
Pages (from-to)85-100
Number of pages16
JournalExperimental Neurology
Volume193
Issue number1
DOIs
StatePublished - May 2005
Externally publishedYes

Fingerprint

Bone Neoplasms
Nerve Fibers
Wounds and Injuries
Neoplasms
Sensory Receptor Cells
Femur
Bone and Bones
Spinal Ganglia
Chronic Pain
Cancer Pain
Activating Transcription Factor 3
Up-Regulation
Galanin
Pain
Peripheral Nerve Injuries
Glial Fibrillary Acidic Protein
Neuralgia
Hypertrophy
Opioid Analgesics
Spinal Cord

Keywords

  • Gabapentin
  • Metastasis
  • Nerve injury
  • Nociception
  • Skeletal malignancies
  • Tumor

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

Cite this

Peters, C. M., Ghilardi, J. R., Keyser, C. P., Kubota, K., Lindsay, T. H., Luger, N. M., ... Mantyh, P. W. (2005). Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. Experimental Neurology, 193(1), 85-100. https://doi.org/10.1016/j.expneurol.2004.11.028

Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. / Peters, Christopher M.; Ghilardi, Joseph R.; Keyser, Cathy P.; Kubota, Kazufumi; Lindsay, Theodore H.; Luger, Nancy M.; Mach, David B.; Schwei, Matthew J.; Sevcik, Molly A.; Mantyh, Patrick W.

In: Experimental Neurology, Vol. 193, No. 1, 05.2005, p. 85-100.

Research output: Contribution to journalArticle

Peters, CM, Ghilardi, JR, Keyser, CP, Kubota, K, Lindsay, TH, Luger, NM, Mach, DB, Schwei, MJ, Sevcik, MA & Mantyh, PW 2005, 'Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain', Experimental Neurology, vol. 193, no. 1, pp. 85-100. https://doi.org/10.1016/j.expneurol.2004.11.028
Peters CM, Ghilardi JR, Keyser CP, Kubota K, Lindsay TH, Luger NM et al. Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. Experimental Neurology. 2005 May;193(1):85-100. https://doi.org/10.1016/j.expneurol.2004.11.028
Peters, Christopher M. ; Ghilardi, Joseph R. ; Keyser, Cathy P. ; Kubota, Kazufumi ; Lindsay, Theodore H. ; Luger, Nancy M. ; Mach, David B. ; Schwei, Matthew J. ; Sevcik, Molly A. ; Mantyh, Patrick W. / Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. In: Experimental Neurology. 2005 ; Vol. 193, No. 1. pp. 85-100.
@article{c1cb3e5f0a1c4daa9205f415ff4da3d7,
title = "Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain",
abstract = "Bone is the most common site of chronic pain in patients with metastatic cancer. What remains unclear are the mechanisms that generate this pain and why bone cancer pain can be so severe and refractory to treatment with opioids. Here we show that following injection and confinement of NCTC 2472 osteolytic tumor cells within the mouse femur, tumor cells sensitize and injure the unmyelinated and myelinated sensory fibers that innervate the marrow and mineralized bone. This tumor-induced injury of sensory nerve fibers is accompanied by an increase in ongoing and movement-evoked pain behaviors, an upregulation of activating transcription factor 3 (ATF3) and galanin by sensory neurons that innervate the tumor-bearing femur, upregulation of glial fibrillary acidic protein (GFAP) and hypertrophy of satellite cells surrounding sensory neuron cell bodies within the ipsilateral dorsal root ganglia (DRG), and macrophage infiltration of the DRG ipsilateral to the tumor-bearing femur. Similar neurochemical changes have been described following peripheral nerve injury and in other non-cancerous neuropathic pain states. Chronic treatment with gabapentin did not influence tumor growth, tumor-induced bone destruction or the tumor-induced neurochemical reorganization that occurs in sensory neurons or the spinal cord, but it did attenuate both ongoing and movement-evoked bone cancer-related pain behaviors. These results suggest that even when the tumor is confined within the bone, a component of bone cancer pain is due to tumor-induced injury to primary afferent nerve fibers that innervate the tumor-bearing bone. Tumor-derived, inflammatory, and neuropathic mechanisms may therefore be simultaneously driving this chronic pain state.",
keywords = "Gabapentin, Metastasis, Nerve injury, Nociception, Skeletal malignancies, Tumor",
author = "Peters, {Christopher M.} and Ghilardi, {Joseph R.} and Keyser, {Cathy P.} and Kazufumi Kubota and Lindsay, {Theodore H.} and Luger, {Nancy M.} and Mach, {David B.} and Schwei, {Matthew J.} and Sevcik, {Molly A.} and Mantyh, {Patrick W}",
year = "2005",
month = "5",
doi = "10.1016/j.expneurol.2004.11.028",
language = "English (US)",
volume = "193",
pages = "85--100",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain

AU - Peters, Christopher M.

AU - Ghilardi, Joseph R.

AU - Keyser, Cathy P.

AU - Kubota, Kazufumi

AU - Lindsay, Theodore H.

AU - Luger, Nancy M.

AU - Mach, David B.

AU - Schwei, Matthew J.

AU - Sevcik, Molly A.

AU - Mantyh, Patrick W

PY - 2005/5

Y1 - 2005/5

N2 - Bone is the most common site of chronic pain in patients with metastatic cancer. What remains unclear are the mechanisms that generate this pain and why bone cancer pain can be so severe and refractory to treatment with opioids. Here we show that following injection and confinement of NCTC 2472 osteolytic tumor cells within the mouse femur, tumor cells sensitize and injure the unmyelinated and myelinated sensory fibers that innervate the marrow and mineralized bone. This tumor-induced injury of sensory nerve fibers is accompanied by an increase in ongoing and movement-evoked pain behaviors, an upregulation of activating transcription factor 3 (ATF3) and galanin by sensory neurons that innervate the tumor-bearing femur, upregulation of glial fibrillary acidic protein (GFAP) and hypertrophy of satellite cells surrounding sensory neuron cell bodies within the ipsilateral dorsal root ganglia (DRG), and macrophage infiltration of the DRG ipsilateral to the tumor-bearing femur. Similar neurochemical changes have been described following peripheral nerve injury and in other non-cancerous neuropathic pain states. Chronic treatment with gabapentin did not influence tumor growth, tumor-induced bone destruction or the tumor-induced neurochemical reorganization that occurs in sensory neurons or the spinal cord, but it did attenuate both ongoing and movement-evoked bone cancer-related pain behaviors. These results suggest that even when the tumor is confined within the bone, a component of bone cancer pain is due to tumor-induced injury to primary afferent nerve fibers that innervate the tumor-bearing bone. Tumor-derived, inflammatory, and neuropathic mechanisms may therefore be simultaneously driving this chronic pain state.

AB - Bone is the most common site of chronic pain in patients with metastatic cancer. What remains unclear are the mechanisms that generate this pain and why bone cancer pain can be so severe and refractory to treatment with opioids. Here we show that following injection and confinement of NCTC 2472 osteolytic tumor cells within the mouse femur, tumor cells sensitize and injure the unmyelinated and myelinated sensory fibers that innervate the marrow and mineralized bone. This tumor-induced injury of sensory nerve fibers is accompanied by an increase in ongoing and movement-evoked pain behaviors, an upregulation of activating transcription factor 3 (ATF3) and galanin by sensory neurons that innervate the tumor-bearing femur, upregulation of glial fibrillary acidic protein (GFAP) and hypertrophy of satellite cells surrounding sensory neuron cell bodies within the ipsilateral dorsal root ganglia (DRG), and macrophage infiltration of the DRG ipsilateral to the tumor-bearing femur. Similar neurochemical changes have been described following peripheral nerve injury and in other non-cancerous neuropathic pain states. Chronic treatment with gabapentin did not influence tumor growth, tumor-induced bone destruction or the tumor-induced neurochemical reorganization that occurs in sensory neurons or the spinal cord, but it did attenuate both ongoing and movement-evoked bone cancer-related pain behaviors. These results suggest that even when the tumor is confined within the bone, a component of bone cancer pain is due to tumor-induced injury to primary afferent nerve fibers that innervate the tumor-bearing bone. Tumor-derived, inflammatory, and neuropathic mechanisms may therefore be simultaneously driving this chronic pain state.

KW - Gabapentin

KW - Metastasis

KW - Nerve injury

KW - Nociception

KW - Skeletal malignancies

KW - Tumor

UR - http://www.scopus.com/inward/record.url?scp=20144387562&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20144387562&partnerID=8YFLogxK

U2 - 10.1016/j.expneurol.2004.11.028

DO - 10.1016/j.expneurol.2004.11.028

M3 - Article

C2 - 15817267

AN - SCOPUS:20144387562

VL - 193

SP - 85

EP - 100

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 1

ER -