Contribution of the tetrodotoxin-resistant voltage-gated sodium channel Na _V 1.9 to sensory transmission and nociceptive behavior

Abstract

The transmission of pain signals after injury or inflammation depends in part on increased excitability of primary sensory neurons. Nociceptive neurons express multiple subtypes of voltagegated sodium channels (Na V1s), each of which possesses unique features that may influence primary afferent excitability. Here, we examined the contribution of Na V1.9 to nociceptive signaling by studying the electrophysiological and behavioral phenotypes of mice with a disruption of the SCN11A gene, which encodes Na V 1.9. Our results confirm that Na V1.9 underlies the persistent tetrodotoxin-resistant current in small-diameter dorsal root ganglion neurons but suggest that this current contributes little to mechanical thermal responsiveness in the absence of injury or to mechanical hypersensitivity after nerve injury or inflammation. However, the expression of Na V1.9 contributes to the persistent thermal hypersensitivity and spontaneous pain behavior after peripheral inflammation. These results suggest that inflammatory mediators modify the function of NaV1.9 to maintain inflammation-induced hyperalgesia.T he generation and propagation of action potentials in sensory neurons depends on the activity of voltage-gated sodium channels (Na V 1s). The differential expression of Na V 1 subtypes in distinct classes of sensory neurons, combined with their unique biophysical properties, suggest specific roles for each subtype in sensory transmission. Sodium channels in sensory neurons can be classified pharmacologically as sensitive to block by low nanomolar concentrations of tetrodotoxin (TTX) or resistant to Ͼ1 M TTX (1, 2).The contribution of TTX-resistant Na V 1 channel subtypes to the transmission of pain signals is an important area of focus: TTXresistant current carries the majority of charge during action potentials in nociceptive neurons (3), and this current is dynamically regulated in response to injury (4, 5). Na V 1.8, expressed primarily in C-fibers (6), underlies a TTX-resistant current with a high threshold for activation and steady-state inactivation and slow kinetics (7). Comparisons between dorsal root ganglion (DRG) neurons from WT and Na V 1.8 null mutant (Ϫ͞Ϫ) mice suggest that Na V 1.8 contributes the majority of the inward current flowing during action potentials in small-diameter neurons (8). Antisense oligonucleotides directed against Na V 1.8 implicate this channel in both neuropathic (9) and inflammatory (10) pain conditions in rats, although Na V 1.8Ϫ͞Ϫ mice displayed only a mild phenotype (7,11).The functional role of Na V 1.9, another subtype selectively expressed in nociceptors (12), remains poorly defined. The primary sequence of Na V 1.9 predicts that this subtype conducts sodium currents resistant to TTX (13). Indeed, a second TTX-resistant current is present in DRG neurons from Na V 1.8 knockout mice (14). This current has been referred to as the persistent, TTXresistant current because of its negative threshold for activation and depolarized midpoint of inactivation, resulting in a significant windo...

Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

“…However, if antisense oligonucleotides to Na v 1.9 or genetic ablation of Na v 1.9 are employed, there appears to be no effect on thermal or mechanical hypersensitivity in the neuropathic rat (Porreca et al, 1999;Priest et al, 2005;Amaya et al, 2006). Interestingly, it appears that Na v 1.9 does play a role in hypersensitivity produced by the application of inflammatory mediators to the peripheral terminals of the nociceptors (Amaya et al, 2006).…”

“…Evidence of a direct role of Na v 1.9 in the development of thermal and mechanical hyperalgesia is lacking in rats with neuropathic pain states (Porecca et al, 1999;Priest et al, 2005). Although still debated (Hillsley et al, 2006), Na v 1.9 may play a significant role in the increased excitability of nociceptive axons during inflammation (Herzog et al, 2001;Baker et al, 2003;Rush and Waxman, 2004;Priest et al, 2005).…”

Na+ Channel Scn1b Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo

“…The TTX-S component was obtained (lower traces) by digitally subtracting the TTX-R I Na from the total I Na B, average peak I Na density-voltage relationships for TTX-R I Na values (circles) and TTX-S I Na values (squares) of small fast DRG neurons, WT (closed symbols, n ϭ 13) or types (not shown). These results suggested that Scn1b deletion may affect the expression or subcellular localization of the VGSC known to be responsible for persistent or slow inactivating I Na in DRG neurons, Na v 1.9 (24).…”

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report

“…Moreover, Nav1.9 channel is also an important regulator of afferent sensitivity in visceral pain pathways to mechanical and inflammatory stimuli, so it could represent an important therapeutic target also for the treatment of visceral pain. A mutation in the gene has also been found in patients with congenital 'indifference' to pain, but in contrast to loss of function SCN9A mutations in this condition, SCN11A mutations are associated with a gain of function with sustained depolarisation of nociceptors impeding the generation of action potentials 27 .…”

“…The role of Nav1.9 channel in pain mechanisms is still under investigation, as Leipold et al identified a specific de novo mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations 26 , and its experimental deletion (Nav1.9-null) was shown either to diminish 27 , or had no effect 28 on thermal pain hypersensitivity produced in knock-out mice. Nevertheless, it plays a key role in the generation of heat and mechanical pain hypersensitivity, both in subacute and chronic inflammatory pain models, suggesting that it may represent a suitable pharmacological target for inflammatory pain care.…”