Proceedings of The Physiological Society

King's College London (2011) Proc Physiol Soc 22, PC14

Poster Communications

Chronic inflammation increases hyperpolarization-activated current in C-, but not A+

X. Weng1, L. Djouhri1

1. University of Liverpool, Liverpool, United Kingdom.


Hypersensitivity to painful stimuli (hyperalgesia) and/or normally non-painful stimuli (allodynia) is a hallmark of inflammation. This inflammatory pain hypersensitivity results partly from increased excitability of nociceptive dorsal root ganglion (DRG) neurons innervating inflamed tissue. These sensitized neurons exhibit increased spontaneous activity (SA) and decreased activation threshold (Woolf & Ma, 2007). The underlying molecular and ionic mechanisms of SA and hyperexcitability in these neurons are poorly understood. Hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are key modulators of neuronal activity by producing the depolarizing Ih current (Biel et al. 2009) which has been implicated in nerve injury-induced hyperexcitability in DRG neurons (Chaplan et al. 2003). Here we examined whether, after tissue inflammation, expression and/or activation properties of Ih change in nociceptive DRG neurons. Hindlimb inflammation was induced by a 150μl intradermal injection of complete Freund’s adjuvant (CFA) into the plantar surface of the left hindpaws of Wistar rats. Discontinuous single electrode voltage clamp (dSEVC) was performed in untreated (control) and CFA treated rats deeply anaesthetised with sodium pentobarbitone (60 mg/kg, i.p.). C-and Aδ-fibre nociceptors were identified on the basis of their dorsal root conduction velocities and their responses to noxious mechanical and thermal stimuli. Ih was assessed with 1 sec hyperpolarizing voltage steps from resting potential to -130 mV and was identified in vivo on the basis of its activation properties, time-dependant rectification, reversal potential, and blockade with Ih antagonist ZD7288 in some neurons. Ih was considered to be present if it was >50 pA. Interestingly 5-7 days after CFA induced inflammation a significantly higher proportion of C-nociceptors in CFA rats expressed Ih compared to control (76% (38/50) vs 48% (21/43), p<0.01, Fisher’s exact test). Furthermore, CFA inflammation induced significant increases in the median Ih amplitude in these neurons (0.21 nA (CFA, n=50) vs 0.03 nA (normal, n=43), P<0.0001 Mann-Whitney U test), the median Ih density (2.91 pA/pF (CFA) vs 0.68 pA/pF (normal), p<0.01) and the rate, but not voltage dependence, of Ih activation. In contrast, there was no change in Ih expression or function in Aδ-fibre nociceptors. These results suggest that Ih/HCN channels are involved in inflammation-induced hyperexcitability of C-nociceptive DRG neurons.

Where applicable, experiments conform with Society ethical requirements