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Chronic inflammatory pain is associated with increased excitability and hyperpolarization-activated current (Ih) in C- but not Aδ-nociceptors.
Pain. 2012 Apr; 153(4):900-914.PAIN

Abstract

Inflammatory pain hypersensitivity results partly from hyperexcitability of nociceptive (damage-sensing) dorsal root ganglion (DRG) neurons innervating inflamed tissue. However, most of the evidence for this is derived from experiments using acute inflammatory states. Herein, we used several approaches to examine the impact of chronic or persistent inflammation on the excitability of nociceptive DRG neurons and on their expression of I(h) and the underlying hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which regulate neuronal excitability. Using in vivo intracellular recordings of somatic action potentials from L4/L5 DRG neurons in normal rats and rats with hindlimb inflammation induced by complete Freund's adjuvant (CFA), we demonstrate increased excitability of C- but not Aδ-nociceptors, 5 to 7 days after CFA. This included an afterdischarge response to noxious pinch, which may contribute to inflammatory mechanohyperalgesia, and increased incidence of spontaneous activity (SA) and decreased electrical thresholds, which are likely to contribute to spontaneous pain and nociceptor sensitization, respectively. We also show, using voltage clamp in vivo, immunohistochemistry and behavioral assays that (1) the inflammation-induced nociceptor hyperexcitability is associated, in C- but not Aδ-nociceptors, with increases in the mean I(h) amplitude/density and in the proportion of I(h) expressing neurons, (2) increased proportion of small DRG neurons (mainly IB4-negative) expressing HCN2 but not HCN1 or HCN3 channel protein, (3) increased HCN2- immunoreactivity in the spinal dorsal horn, and (4) attenuation of inflammatory mechanoallodynia with the selective I(h) antagonist, ZD7288. Taken together, the findings suggest that C- but not Aδ-nociceptors sustain chronic inflammatory pain and that I(h)/HCN2 channels contribute to inflammation-induced C-nociceptor hyperexcitability.

Authors+Show Affiliations

Department of Clinical and Molecular Pharmacology, Institute of Translational Medicine, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22377439

Citation

Weng, Xiechuan, et al. "Chronic Inflammatory Pain Is Associated With Increased Excitability and Hyperpolarization-activated Current (Ih) in C- but Not Aδ-nociceptors." Pain, vol. 153, no. 4, 2012, pp. 900-914.
Weng X, Smith T, Sathish J, et al. Chronic inflammatory pain is associated with increased excitability and hyperpolarization-activated current (Ih) in C- but not Aδ-nociceptors. Pain. 2012;153(4):900-914.
Weng, X., Smith, T., Sathish, J., & Djouhri, L. (2012). Chronic inflammatory pain is associated with increased excitability and hyperpolarization-activated current (Ih) in C- but not Aδ-nociceptors. Pain, 153(4), 900-914. https://doi.org/10.1016/j.pain.2012.01.019
Weng X, et al. Chronic Inflammatory Pain Is Associated With Increased Excitability and Hyperpolarization-activated Current (Ih) in C- but Not Aδ-nociceptors. Pain. 2012;153(4):900-914. PubMed PMID: 22377439.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic inflammatory pain is associated with increased excitability and hyperpolarization-activated current (Ih) in C- but not Aδ-nociceptors. AU - Weng,Xiechuan, AU - Smith,Trevor, AU - Sathish,Jean, AU - Djouhri,Laiche, Y1 - 2012/02/28/ PY - 2011/06/07/received PY - 2011/11/30/revised PY - 2012/01/18/accepted PY - 2012/3/2/entrez PY - 2012/3/2/pubmed PY - 2012/9/13/medline SP - 900 EP - 914 JF - Pain JO - Pain VL - 153 IS - 4 N2 - Inflammatory pain hypersensitivity results partly from hyperexcitability of nociceptive (damage-sensing) dorsal root ganglion (DRG) neurons innervating inflamed tissue. However, most of the evidence for this is derived from experiments using acute inflammatory states. Herein, we used several approaches to examine the impact of chronic or persistent inflammation on the excitability of nociceptive DRG neurons and on their expression of I(h) and the underlying hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which regulate neuronal excitability. Using in vivo intracellular recordings of somatic action potentials from L4/L5 DRG neurons in normal rats and rats with hindlimb inflammation induced by complete Freund's adjuvant (CFA), we demonstrate increased excitability of C- but not Aδ-nociceptors, 5 to 7 days after CFA. This included an afterdischarge response to noxious pinch, which may contribute to inflammatory mechanohyperalgesia, and increased incidence of spontaneous activity (SA) and decreased electrical thresholds, which are likely to contribute to spontaneous pain and nociceptor sensitization, respectively. We also show, using voltage clamp in vivo, immunohistochemistry and behavioral assays that (1) the inflammation-induced nociceptor hyperexcitability is associated, in C- but not Aδ-nociceptors, with increases in the mean I(h) amplitude/density and in the proportion of I(h) expressing neurons, (2) increased proportion of small DRG neurons (mainly IB4-negative) expressing HCN2 but not HCN1 or HCN3 channel protein, (3) increased HCN2- immunoreactivity in the spinal dorsal horn, and (4) attenuation of inflammatory mechanoallodynia with the selective I(h) antagonist, ZD7288. Taken together, the findings suggest that C- but not Aδ-nociceptors sustain chronic inflammatory pain and that I(h)/HCN2 channels contribute to inflammation-induced C-nociceptor hyperexcitability. SN - 1872-6623 UR - https://www.unboundmedicine.com/medline/citation/22377439/Chronic_inflammatory_pain_is_associated_with_increased_excitability_and_hyperpolarization_activated_current__Ih__in_C__but_not_Aδ_nociceptors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/00006396-201204000-00026 DB - PRIME DP - Unbound Medicine ER -