Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: A mechanism for the development of chronic sensitization of peripheral nociceptors

Sonia Bhangoo, Dongjun Ren, Richard J. Miller, Kenneth J. Henry, Jayana Lineswala, Chafiq Hamdouchi, Baolin Li, Patrick E. Monahan, David M. Chan, Matthew S. Ripsch, Fletcher White

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

Background: Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats. Results: Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon γ-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1α (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca2+]i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia. Conclusion: These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.

Original languageEnglish (US)
Article number38
JournalMolecular Pain
Volume3
DOIs
StatePublished - Dec 12 2007
Externally publishedYes

Fingerprint

Nociceptors
Chemokine Receptors
Demyelinating Diseases
Sensory Receptor Cells
CCR2 Receptors
Nociceptive Pain
Chemokine CCL5
Lysophosphatidylcholines
Chemokines
Chronic Pain
Chemokine CXCL12
CXC Chemokines
Pain
Polyneuropathies
Chemokine CCL2
Hyperalgesia
Wounds and Injuries
Sciatic Nerve
Intraperitoneal Injections
Peripheral Nerves

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Molecular Medicine
  • Cellular and Molecular Neuroscience

Cite this

Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat : A mechanism for the development of chronic sensitization of peripheral nociceptors. / Bhangoo, Sonia; Ren, Dongjun; Miller, Richard J.; Henry, Kenneth J.; Lineswala, Jayana; Hamdouchi, Chafiq; Li, Baolin; Monahan, Patrick E.; Chan, David M.; Ripsch, Matthew S.; White, Fletcher.

In: Molecular Pain, Vol. 3, 38, 12.12.2007.

Research output: Contribution to journalArticle

Bhangoo, Sonia ; Ren, Dongjun ; Miller, Richard J. ; Henry, Kenneth J. ; Lineswala, Jayana ; Hamdouchi, Chafiq ; Li, Baolin ; Monahan, Patrick E. ; Chan, David M. ; Ripsch, Matthew S. ; White, Fletcher. / Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat : A mechanism for the development of chronic sensitization of peripheral nociceptors. In: Molecular Pain. 2007 ; Vol. 3.
@article{1a085b9a5a27442fbaf668619d1fa13e,
title = "Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: A mechanism for the development of chronic sensitization of peripheral nociceptors",
abstract = "Background: Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats. Results: Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon γ-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1α (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca2+]i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia. Conclusion: These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.",
author = "Sonia Bhangoo and Dongjun Ren and Miller, {Richard J.} and Henry, {Kenneth J.} and Jayana Lineswala and Chafiq Hamdouchi and Baolin Li and Monahan, {Patrick E.} and Chan, {David M.} and Ripsch, {Matthew S.} and Fletcher White",
year = "2007",
month = "12",
day = "12",
doi = "10.1186/1744-8069-3-38",
language = "English (US)",
volume = "3",
journal = "Molecular Pain",
issn = "1744-8069",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat

T2 - A mechanism for the development of chronic sensitization of peripheral nociceptors

AU - Bhangoo, Sonia

AU - Ren, Dongjun

AU - Miller, Richard J.

AU - Henry, Kenneth J.

AU - Lineswala, Jayana

AU - Hamdouchi, Chafiq

AU - Li, Baolin

AU - Monahan, Patrick E.

AU - Chan, David M.

AU - Ripsch, Matthew S.

AU - White, Fletcher

PY - 2007/12/12

Y1 - 2007/12/12

N2 - Background: Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats. Results: Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon γ-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1α (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca2+]i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia. Conclusion: These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.

AB - Background: Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats. Results: Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon γ-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1α (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca2+]i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia. Conclusion: These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.

UR - http://www.scopus.com/inward/record.url?scp=39049085666&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39049085666&partnerID=8YFLogxK

U2 - 10.1186/1744-8069-3-38

DO - 10.1186/1744-8069-3-38

M3 - Article

C2 - 18076762

AN - SCOPUS:39049085666

VL - 3

JO - Molecular Pain

JF - Molecular Pain

SN - 1744-8069

M1 - 38

ER -