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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.
Pubmed ID: 18270172
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NEURON is a simulation environment for modeling individual neurons and networks of neurons. It provides tools for conveniently building, managing, and using models in a way that is numerically sound and computationally efficient. It is particularly well-suited to problems that are closely linked to experimental data, especially those that involve cells with complex anatomical and biophysical properties. NEURON has benefited from judicious revision and selective enhancement, guided by feedback from the growing number of neuroscientists who have used it to incorporate empirically-based modeling into their research strategies. NEURON's computational engine employs special algorithms that achieve high efficiency by exploiting the structure of the equations that describe neuronal properties. It has functions that are tailored for conveniently controlling simulations, and presenting the results of real neurophysiological problems graphically in ways that are quickly and intuitively grasped. Instead of forcing users to reformulate their conceptual models to fit the requirements of a general purpose simulator, NEURON is designed to let them deal directly with familiar neuroscience concepts. Consequently, users can think in terms of the biophysical properties of membrane and cytoplasm, the branched architecture of neurons, and the effects of synaptic communication between cells. * helps users focus on important biological issues rather than purely computational concerns * has a convenient user interface * has a user-extendable library of biophysical mechanisms * has many enhancements for efficient network modeling * offers customizable initialization and simulation flow control * is widely used in neuroscience research by experimentalists and theoreticians * is well-documented and actively supported * is free, open source, and runs on (almost) everything
View all literature mentionsSoftware suite for electrophysiology data acquisition and analysis by Molecular Devices. Used for the control and recording of voltage clamp, current clamp, and patch clamp experiments. The software suite consists of Clampex 11 Software for data acquisition, AxoScope 11 Software for background recording, Clampfit 11 Software for data analysis, and optional Clampfit Advanced Analysis Module for sophisticated and streamlined analysis.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionslaboratory mouse with name 129P2/OlaHsd from MGI.
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