Evidence of a physiological role for use-dependent inactivation of NaV1.8 sodium channels

Ever since reports of tetrodotoxin-resistant (TTX-r) Na+ currents in mammalian sensory neurons came to light some 30 years ago there has been a concerted effort to characterize the underlying channels and understand their physiological roles in the transmission of sensory information. Much of this research has been driven by the fact that TTX-r Na+ channels are expressed by most nociceptors but not (for the most part) by other types of neurons in the peripheral and central nervous system. Thus a better understanding of these channels could lead to advances in the development of selective medicines to treat pain. Molecular biologists have cloned several distinct types of TTX-r Na+ channels. One type, designated NaV1.8, makes a significant contribution to somatic action potentials in nociceptors, and numerous studies suggest that NaV1.8 channels play an important role in nociceptor sensitization by inflammatory mediators such as prostaglandin E2 and serotonin. However, most experiments on NaV1.8 channel function and modulation have been carried out on small dorsal root ganglion (DRG) cell bodies assumed to represent nociceptors, and Na+ channels at this location do not participate directly in sensory transmission. On the other hand, it has been shown that TTX-r Na+ channels (probably NaV1.8) support action potentials travelling in the distal region of axons near the peripheral sensory receptors of nociceptors innervating rat cranial meninges, rat paw and guinea pig cornea. However, until recently, there has only been speculation regarding the physiological roles of these axonal TTX-r channels. In this issue of The Journal of Physiology, De Col et al. (2008) report novel data suggesting that NaV1.8 channels play an important role in the activity-dependent slowing of conduction velocity along the axons of nociceptors innervating rat cranial meninges. The phrase ‘activity-dependent slowing of conduction velocity’ refers to a gradual decrease in conduction velocity in response to repetitive stimuli delivered at around 1–4 Hz. The initial thrust of the De Col et al. (2008) study was to dispel an old, entrenched idea that the activity-dependent slowing of conduction velocity in unmyelinated axons is due to enhancement of the Na+–K+-ATPase. They show that blockade of this pump does not block activity-dependent slowing of conduction velocity. De Col et al. (2008) also demonstrate that reduction of the number of available TTX-sensitive channels with TTX does not interfere with the activity-dependent slowing of conduction velocity. These observations lead to the hypothesis that the activity-dependent slowing of conduction velocity is mediated by the use-dependent inactivation of TTX-r Na+ channels. This hypothesis fits well with the observation that NaV1.8 channels exhibit a greater tendency to enter a slowly recovered inactivation state than TTX-sensitive channels expressed in nociceptor-like DRG cell bodies (Rush et al. 1998). A significant fraction of NaV1.8 channels are induced into the slowly recovered inactivation state by action potentials at typical nociceptor firing frequencies (Tripathi et al. 2006). Thus it seems possible that most TTX-sensitive Na+ channels recover completely from inactivation within the interstimulus intervals imposed in the De Col et al. (2008) study, while the fraction of NaV1.8 channels residing in the slow inactivated state increases over time. In addition to providing the first good evidence of a physiological role for use-dependent inactivation of NaV1.8 channels in the transmission of nociceptive information, the De Col et al. (2008) study has considerable clinical implications. There have been several reports that certain analgesic and anticonvulsant drugs, including lidocaine and carbamazepine, target slow inactivated NaV1.8 channels (Cardenas et al. 2006; Leffler et al. 2007). That NaV1.8 channels enter this state more readily than TTX-sensitive Na+ channels could provide a basis for the development of drugs that more selectively target nociceptors. The finding that slow inactivation of axonal NaV1.8 channels may act as a bottle neck to the transmission of nociceptive information should provide impetus to the search for such drugs. In the light of previous studies, De Col et al. (2008) report begs several questions. There is considerable variation among DRG cell bodies regarding the degree of use-dependent inactivation of NaV1.8 channels (Rush et al. 1998; Tripathi et al. 2006). Is there a corresponding variation regarding axonal NaV1.8 channels expressed by different types of nociceptors? What is the purpose of activity-dependent slowing of conduction velocity, and how would variation in this phenomenon cause different types of nociceptors to behave in ways that enhance survival? How would up-regulation of NaV1.8 channel activity by inflammatory mediators affect activity-dependent slowing of conduction velocity? Certain analgesics produce a greater block of NaV1.8 currents that exhibit more use-dependent inactivation than NaV1.8 currents that exhibit less use-dependent inactivation (Cardenas et al. 2006). Would nociceptors that vary regarding activity-dependent slowing of conduction velocity also vary in their susceptibility to analgesics that target slow inactivated NaV1.8 channels? The De Col et al. (2008) study will stimulate much future research aimed at answering such questions.