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Altered function of [Na.sup.+] channels is responsible for increased hyperexcitability of primary afferent neurons that may underlie pathological pain states. Recent evidence suggests that the Navl.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.sup.+] 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.sup.+] 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 CsC1- and KCl-based pipette solutions, whether C-protein signaling pathways and inflammatory mediators upregulate the NaN/Nav1.9 current. Bradykinin, ATE 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.

Byline: J. Titze (1), I. M. Larina (2), K. Garib (3), K. O. Kirsch (4), A. Maye (5), R. Lang (1), H. K. Gunga (4), B. Johanes (4), H. Gochlen-Koch (6), E. Kim (3) Abstract: According to the generally accepted view, sodium accumulation in the human body takes place in the extracellular space and is accompanied by an increase in the rate of fluid retention and body weight gain. However, this view was revised in recent studies, which demonstrated that sodium could be accumulated in the human body without expansion of the extracellular space. Sodium exchange and its effect on body weight (BW) were investigated in long-term balance studies. Three apparently healthy volunteer subjects were confined for 135 days to a ground-based model of the main unit of the Mir space station, where they were exposed to model conditions similar to conditions of actual long-term spaceflight. The daily balance of sodium and its contribution to BW changes were studied. During the period of observation, the subjects accumulated 2.973--7.324 mmol of sodium and gained 5.1--9.3 kg. Initially, there was a positive correlation between changes in the total body sodium and the BW, which reflected sodium-dependent extracellular space expansion. However, by the end of the period of isolation, the relative rate of body weight gain was lower than the relative rate of gain in the total body sodium, which suggested that sodium accumulated in an osmotically inactive form. The fact that sodium accumulated without BW gain suggests that isolation of healthy subjects in a hermetically sealed enclosure stimulates sodium accumulation in the body in an osmotically inactive form. The sodium-storing processes activated under these conditions might be localized in bone, connective tissue (skin), or cartilage. Rhythmic variation in the net sodium balance was observed and attributed to oscillations of renal excretion of aldosterone. It is obvious that the depot of osmotically inactive sodium should be taken into account in studies of cardiovascular system function and in pathophysiological approaches to edematous syndrome and hypertension. Author Affiliation: (1) Department of Nephrology, Free University of Berlin, Friedrich-Alexander-University, Erlangen-Nurnberg, Germany (2) Russian Academy of Sciences, State Research Center Institute of Biomedical Problems, Khoroshevskoe sh. 76a, Moscow, 123007, Russia (3) Faculte de Medecine Lyon, Laboratoire de Physiologie de l'Environnement (GIP Exercise), Grange-Blanche 8, Lyon, France (4) Department of Physiology, Free University of Berlin, Friedrich-Alexander-University, Erlangen-Nurnberg, Germany (5) MEDES-Clinique Spatiale, CHU-Rangueil, Toulouse, France (6) Centre National d'Etudes Spatiales, Paris, 80 route de Biot (formerly CARRAR), Valbonne, France Article History: Registration Date: 11/10/2004