title: Chronic inflammatory pain is associated with increased excitability and hyperpolarization-activated current (Ih) in C- but not Aδ-nociceptors.
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.affiliation: Department of Clinical and Molecular Pharmacology, Institute of Translational Medicine, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.
authors.forename: Xiechuan
authors.initials: X
authors.lastname: Weng
authors.forename: Trevor
authors.initials: T
authors.lastname: Smith
authors.forename: Jean
authors.initials: J
authors.lastname: Sathish
authors.forename: Laiche
authors.initials: L
authors.lastname: Djouhri
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D059350:Chronic Pain / Q000473:pathology / Q000503:physiopathology*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000502:physiology; D005260:Female; D006930:Hyperalgesia / Q000503:physiopathology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D018836:Inflammation Mediators / Q000502:physiology*; D007473:Ion Channels / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology*; D010147:Pain Measurement / Q000379:methods*; D015221:Potassium Channels; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000502:physiology*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C578712:Hcn2 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D018836:Inflammation Mediators; D007473:Ion Channels; D015221:Potassium Channels; D017465:Receptors, Opioid, delta