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1.  Nav1.9 Channel Contributes to Mechanical and Heat Pain Hypersensitivity Induced by Subacute and Chronic Inflammation 
PLoS ONE  2011;6(8):e23083.
Inflammation is known to be responsible for the sensitization of peripheral sensory neurons, leading to spontaneous pain and invalidating pain hypersensitivity. Given its role in regulating neuronal excitability, the voltage-gated Nav1.9 channel is a potential target for the treatment of pathological pain, but its implication in inflammatory pain is yet not fully described. In the present study, we examined the role of the Nav1.9 channel in acute, subacute and chronic inflammatory pain using Nav1.9-null mice and Nav1.9 knock-down rats. In mice we found that, although the Nav1.9 channel does not contribute to basal pain thresholds, it plays an important role in heat pain hypersensitivity induced by subacute paw inflammation (intraplantar carrageenan) and chronic ankle inflammation (complete Freund's adjuvant-induced monoarthritis). We showed for the first time that Nav1.9 also contributes to mechanical hypersensitivity in both models, as assessed using von Frey and dynamic weight bearing tests. Consistently, antisense-based Nav1.9 gene silencing in rats reduced carrageenan-induced heat and mechanical pain hypersensitivity. While no changes in Nav1.9 mRNA levels were detected in dorsal root ganglia (DRGs) during subacute and chronic inflammation, a significant increase in Nav1.9 immunoreactivity was observed in ipsilateral DRGs 24 hours following carrageenan injection. This was correlated with an increase in Nav1.9 immunolabeling in nerve fibers surrounding the inflamed area. No change in Nav1.9 current density could be detected in the soma of retrolabeled DRG neurons innervating inflamed tissues, suggesting that newly produced channels may be non-functional at this level and rather contribute to the observed increase in axonal transport. Our results provide evidence that Nav1.9 plays a crucial role in the generation of heat and mechanical pain hypersensitivity, both in subacute and chronic inflammatory pain models, and bring new elements for the understanding of its regulation in those models.
doi:10.1371/journal.pone.0023083
PMCID: PMC3155549  PMID: 21857998
2.  Neurotransmitter modulation of small conductance Ca2+-activated K+ (SK) channels by regulation of Ca2+ gating 
Neuron  2008;59(3):439-449.
Summary
Small-conductance Ca2+-activated K+ (SK) channels are widely expressed in neuronal tissues where they underlie post-spike hyperpolarizations, regulate spike-frequency adaptation and shape synaptic responses. SK channels constitutively interact with calmodulin (CaM), which serves as Ca2+ sensor, and with protein kinase CK2 and protein phosphatase 2A, which modulate their Ca2+ gating. By recording coupled activities of Ca2+ and SK2 channels, we showed that SK2 channels can be inhibited by neurotransmitters independently of changes in the activity of the priming Ca2+ channels. This inhibition involves SK2-associated CK2 and results from a 3-fold reduction in the steady-state Ca2+ sensitivity of channel gating. CK2 phosphorylated SK2-bound CaM but not KCNQ2-bound CaM, thereby selectively regulating Ca2+ gating of SK2 channels. We extended these observations to sensory neurons by showing that noradrenaline inhibits SK current and enhances signaling of primary afferent neurons in a CK2- dependent fashion. Hence, neurotransmitter-initiated signaling cascades can dynamically regulate Ca2+ sensitivity of SK channels and directly influence somatic excitability.
doi:10.1016/j.neuron.2008.05.026
PMCID: PMC2651825  PMID: 18701069
3.  Inflammatory Mediators Increase Nav1.9 Current and Excitability in Nociceptors through a Coincident Detection Mechanism 
The Journal of General Physiology  2008;131(3):211-225.
Altered function of Na+ channels is responsible for increased hyperexcitability of primary afferent neurons that may underlie pathological pain states. Recent evidence suggests that the Nav1.9 subunit is implicated in inflammatory but not acute pain. However, the contribution of Nav1.9 channels to the cellular events underlying nociceptor hyperexcitability is still unknown, and there remains much uncertainty as to the biophysical properties of Nav1.9 current and its modulation by inflammatory mediators. Here, we use gene targeting strategy and computer modeling to identify Nav1.9 channel current signature and its impact on nociceptors' firing patterns. Recordings using internal fluoride in small DRG neurons from wild-type and Nav1.9-null mutant mice demonstrated that Nav1.9 subunits carry the TTX-resistant “persistent” Na+ current called NaN. Nav1.9−/− nociceptors showed no significant change in the properties of the slowly inactivating TTX-resistant SNS/Nav1.8 current. The loss in Nav1.9-mediated Na+ currents was associated with the inability of small DRG neurons to generate a large variety of electrophysiological behaviors, including subthreshold regenerative depolarizations, plateau potentials, active hyperpolarizing responses, oscillatory bursting discharges, and bistable membrane behaviors. We further investigated, using CsCl- and KCl-based pipette solutions, whether G-protein signaling pathways and inflammatory mediators upregulate the NaN/Nav1.9 current. Bradykinin, ATP, histamine, prostaglandin-E2, and norepinephrine, applied separately at maximal concentrations, all failed to modulate the Nav1.9 current. However, when applied conjointly as a soup of inflammatory mediators they rapidly potentiated Nav1.9 channel activity, generating subthreshold amplification and increased excitability. We conclude that Nav1.9 channel, the molecular correlate of the NaN current, is potentiated by the concerted action of inflammatory mediators that may contribute to nociceptors' hyperexcitability during peripheral inflammation.
doi:10.1085/jgp.200709935
PMCID: PMC2248717  PMID: 18270172
4.  Mechanosensor Channels in Mammalian Somatosensory Neurons 
Sensors (Basel, Switzerland)  2007;7(9):1667-1682.
Mechanoreceptive sensory neurons innervating the skin, skeletal muscles and viscera signal both innocuous and noxious information necessary for proprioception, touch and pain. These neurons are responsible for the transduction of mechanical stimuli into action potentials that propagate to the central nervous system. The ability of these cells to detect mechanical stimuli impinging on them relies on the presence of mechanosensitive channels that transduce the external mechanical forces into electrical and chemical signals. Although a great deal of information regarding the molecular and biophysical properties of mechanosensitive channels in prokaryotes has been accumulated over the past two decades, less is known about the mechanosensitive channels necessary for proprioception and the senses of touch and pain. This review summarizes the most pertinent data on mechanosensitive channels of mammalian somatosensory neurons, focusing on their properties, pharmacology and putative identity.
PMCID: PMC3841838
Pain; Touch; Skin sensation; Mechanosensory transduction; Stretch; Osmotic shock; Mechanosensitive channels; TRP channels; ASIC; amiloride; DRG

Results 1-4 (4)