Mechanisms of Sensitization Ion Channels

In order for the membrane depolarization that follows stimulus transduction to impact the CNS, it must be converted into an action potential. This requires another set of specialized proteins referred to as voltage-gated ion channels. These channels are opened or closed in response to changes in membrane potential. Voltage-gated Na+ channels (VGSC) mediate the rapid depolarization of the action potential. VGSCs consist of an a- and up to two P-subunits (70). The a-sub-unit contains the voltage sensor and ion channel. Nine a-subunits have been identified, which differ with respect to their pharmacological sensitivity and biophysical properties. Phosphoryla-tion of VGSC a-subunits results in changes in biophysical properties of the channel (71). P-sub-units also influence the biophysical properties of VGSCs and are instrumental in targeting VGSCs to specific sites in the cell membrane (72). Thus, there are a number of ways in which changes in VGSCs may contribute to the sensitization of nociceptive afferents in the presence of tissue injury or disease. Those that have been observed include (i) changes in the expression of a-subunits (73), (ii) changes in the expression of P-subunits (74,75), (iii) changes in the relative distribution of a-subunits in the cell membrane (76), and (iv) changes in the biophysical properties of VGSCs (77). The relative density of VGSCs available for activation determines action potential threshold, and the ability of a neuron to fire repetitive action potentials. Therefore, an increase in channel density will result in a decrease in action potential threshold and an increase in the neuronal firing frequency. Because P-subunits can increase the rate of channel activation (78), an increase in P-subunit may also decrease action potential threshold as well as the magnitude of the generator potential necessary to reach action potential threshold. Some VGSC a-subunits have a lower threshold for activation than others (76,79), and thus a shift in the relative distribution of a-subunits from high threshold to low threshold would result in a decrease in action potential threshold. Finally, because the biophysical properties such as the voltage dependence of channel activation, the voltage dependence of channel availability, and rates of channel activation and inactivation may be influenced by phosphorylation state of the a-subunit (71), the appropriate changes in channel phosphorylation may also result in decreases in action potential threshold and/or the ability of the channel to sustain multiple action potentials.

Voltage-gated K+ channels (VGPCs) are primarily responsible for membrane repolarization following the depolarization mediated by VGSCs. The density and biophysical properties of VGPCs also influence other aspects of the action potential waveform including action potential threshold and the magnitude and duration of the after hyperpolarization that occurs following an action potential. Other types of K+ channels such as Ca2+-modulated K+ channels [big con-ducatance Ca2+ modulated K+ channel (BK) and small conducatance Ca2+ activated K+ channel (SK)], voltage-independent, or leak K+ channels [i.e., two-pore potassium channels such as TWIK related K+ channel 1 where TWIK stands for tandem of p domains in a weak inward rectifier K+ channel (TREK-1) and TWIK related arachidonic acid stimulated K+ channel (TRAAK)], and ligand-regulated K+ channels [such as KQT related K+ channel (KCNQ) or inward rectifying K+ channel (Kir) channels] may also influence properties of the action potential waveform. Because some of these K+ channels may have a low threshold for activation or even be active at the resting membrane potential, they may influence the extent to which membrane depolarization that occurs following stimulus transduction is able to drive activation of VGSCs, and therefore impact action potential initiation (80). Because these channels may influence the magnitude and/or decay of the afterhyperpolarization, they can influence interspike interval and action potential burst duration (80). Finally, because these channels may influence action potential duration (81), they may have a secondary influence on the amount of Ca2+ that enters the neuron via voltage-gated Ca2+ channels (VGCCs). The amount of Ca2+ entry can again influence the excitability of afferent terminals via Ca2+-modulated K+ channels (82). Ca2+ may also influence transmitter release, which occurs at both peripheral and central terminals of nociceptive afferents. The peripheral release of transmitter may further contribute to nociceptor sensitization via a direct action back on the afferent terminal as well as a secondary facilitation of the inflammatory process (83). In short, a wide variety of K+ channels are able to influence the excitability of nociceptive afferents in a multiplicity of ways. Importantly, both acute (84) and persistent (85-87) changes in K+ channels have been described in response to inflammatory mediators and/or inflammation as well as other forms of tissue injury (88).

As suggested above, VGCCs constitute a third class of ion channels that may also contribute to the sensitization of nociceptor terminals. In addition to their secondary influence on nociceptive excitability via modulation of K+ and Cl_ channels (82,89,90) and transmitter release, there is evidence that VGCCs contribute directly to the sensitization of nociceptive afferents. The most compelling evidence has been obtained for low-threshold, or T-type VGCCs (91,92). Pharmacological evidence suggests that these channels influence action potential threshold and therefore nociceptive threshold (91). There is also evidence that when present in sufficient density, these channels may also mediate a sustained depolarization following action potential initiation that is of sufficient magnitude to induce subsequent action

Box 4 Action Potentials in the Sensory Neuron Cell Body

Researchers have long appreciated that the density of voltage-gated channels in the cell body of sensory ganglia is sufficient to support neural activity. However, because of the T-junction, action potentials may travel from afferent terminal to terminal without invading the sensory neuron cell body. Thus, it was not immediately clear why the density of channels within the cell body should be high enough to support action potential generation. However, recent evidence suggests that action potentials in the sensory neuron cell body may serve several purposes. It turns out that Ca2+ transients associated with neural activity invading the cell body may be critical for regulating transcriptional and translational machinery, and therefore a number of cellular processes such as nerve formation (97). Activity-evoked Ca2+ transients may also be sufficient to drive transmitter release within the ganglia (98), providing a mechanism for "cross talk'' between sensory neurons, which is thought to amplify signals initiated in the periphery (99,100). In the presence of nerve injury, activity may even be initiated from within sensory ganglia, a change thought to contribute to ongoing pain associated with nerve injury (101).

potential generation (93). While the impact of injury on the density, distribution, or properties of low-threshold VGCCs has yet to be investigated in detail (94), there is evidence of both acute (95) and persistent changes in high-threshold VGCCs (94,96).

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