title: Persistent hindlimb inflammation induces changes in activation properties of hyperpolarization-activated current (Ih) in rat C-fiber nociceptors in vivo.
abstract: A hallmark of chronic inflammation is hypersensitivity to noxious and innocuous stimuli. This inflammatory pain hypersensitivity results partly from hyperexcitability of nociceptive dorsal root ganglion (DRG) neurons innervating inflamed tissue, although the underlying ionic mechanisms are not fully understood. However, we have previously shown that the nociceptor hyperexcitability is associated with increased expression of hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) protein and hyperpolarization-activated current (Ih) in C-nociceptors. Here we used in vivo voltage-clamp and current-clamp recordings, in deeply anesthetized rats, to determine whether activation properties of Ih in these C-nociceptors also change following persistent (not acute) hindlimb inflammation induced by complete Freund's adjuvant (CFA). Recordings were made from lumbar (L4/L5) C-nociceptive DRG neurons. Behavioral sensory testing was performed 5-7days after CFA treatment, and all the CFA-treated group showed significant behavioral signs of mechanical and heat hypersensitivity, but not spontaneous pain. Compared with control, C-nociceptors recorded 5-7days after CFA showed: (a) a significant increase in the incidence of spontaneous activity (from ∼5% to 26%) albeit at low rate (0.14±0.08Hz (Mean±SEM); range, 0.01-0.29Hz), (b) a significant increase in the percentage of neurons expressing Ih (from 35%, n=43-84%, n=50) based on the presence of voltage "sag" of >10%, and (c) a significant increase in the conductance (Gh) of the somatic channels conducting Ih along with the corresponding Ih,Ih, activation rate, but not voltage dependence, in C-nociceptors. Given that activation of Ih depolarizes the neuronal membrane toward the threshold of action potential generation, these changes in Ih kinetics in CFA C-nociceptors may contribute to their hyperexcitability and thus to pain hypersensitivity associated with persistent inflammation.
authors.affiliation: Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia.
authors.forename: L
authors.initials: L
authors.lastname: Djouhri
authors.affiliation: Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia.
authors.forename: M
authors.initials: M
authors.lastname: Al Otaibi
authors.affiliation: Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia.
authors.forename: K
authors.initials: K
authors.lastname: Kahlat
authors.affiliation: Wolfson CARD, Neurorestoration Group, Hodgkin Building, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK.
authors.forename: T
authors.initials: T
authors.lastname: Smith
authors.affiliation: Department of Molecular and Clinical Pharmacology;Sherrington Buildings, University of Liverpool, L69 3GE, UK.
authors.forename: J
authors.initials: J
authors.lastname: Sathish
authors.affiliation: Department of Neurobiology and State Key Laboratory of Proteomics, Beijing Institute of B Basic Medical Sciences, Beijing 100850, China. Electronic address: wengxc2000@Hotmail.com.
authors.forename: X
authors.initials: X
authors.lastname: Weng
mesh_terms: D000818:Animals; D005260:Female; D005620:Freund's Adjuvant; D005727:Ganglia, Spinal / Q000503:physiopathology*; D006614:Hindlimb; D006930:Hyperalgesia / Q000503:physiopathology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced; D008564:Membrane Potentials; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D005620:Freund's Adjuvant
keywords: HCN; dorsal root ganglion; inflammatory pain; nociceptors; primary sensory neurons