Membrane Potential Oscillations in Dorsal Root Ganglion Neurons: Role in Normal Electrogenesis and Neuropathic Pain

Abstract

Abnormal afferent discharge originating at ectopic sites in injured primary sensory neurons is thought to be an important generator of paraesthesias, dysaesthesias, and chronic neuropathic pain. We report here that the ability of these neurons to sustain repetitive discharge depends on intrinsic resonant properties of the cell membrane and that the prevalence of this characteristic increases after nerve injury. Recording from primary sensory neurons in excised rat dorsal root ganglia, we found that some cells show subthreshold oscillations in their membrane potential. The amplitude, frequency, and coherence of these oscillations were voltage sensitive. Oscillations gave rise to action potentials when they reached threshold. Indeed, the presence of oscillations proved to be a necessary condition for sustained spiking both at resting membrane potential and on depolarization; neurons without them were incapable of sustained discharge even on deep depolarization. Previous nerve injury increased the proportion of neurons sampled that had subthreshold oscillations, and hence the proportion that generated ectopic spike discharge. Oscillatory behavior and ectopic spiking were eliminated by [Na(+)](o) substitution or bath application of lidocaine or tetrodotoxin (TTX), under conditions that preserved axonal spike propagation. This suggests that a TTX-sensitive Na(+) conductance contributes to the oscillations. Selective pharmacological suppression of subthreshold oscillations may offer a means of controlling neuropathic paraesthesias and pain without blocking afferent nerve conduction.

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

“…The common sciatic nerves at the level of the CCI with or without NT-3 infusion were processed to detect either Na v 1.8 or Na v 1.9 protein. Consistent with previous reports (Devor et al, 1989;England et al, 1994England et al, , 1996Amir et al, 1999), both Na v 1.8 and Na v 1.9 protein levels were more highly localized to the constriction sites 7 days following CCI (CCI; Figure 7 bottom). Infusion of NT-3 attenuated this redistribution as evidenced by a reduction in relative levels of Na v 1.8 and Na v 1.9 protein at the constriction sites of the CCI + NT-3 treated nerves (Figure 7 bottom).…”

“…NT-3 effects a decrease in Na v 1.8 and Na v 1.9 protein in the nerve and neuroma Following nerve injury, voltage gated sodium channels are highly localized/redistributed to the tips of the injured axons and/or neuromas despite a lower level of expression in the cell body of these neurons (Devor et al, 1989;England et al, 1994England et al, , 1996Amir et al, 1999). Thus, we asked whether the dramatic reduction in sodium channel expression effected by NT-3 in neurons ipsilateral to CCI is also reflected in a reduced localization of these channels to the neuroma at the constriction sites formed by the ligatures, unlike that observed for CCI alone.…”

“…It is well established that both the activation threshold of a neuron and the potential for spontaneous firing is regulated by sodium channels (Hodgkin and Huxley, 1952;Catterall, 1995). This hyperexcitability of sensory neurons following nerve injury has been associated with altered expression and the redistribution of voltage gated sodium channels to the tips of the injured axons and/or the neuromas (Devor et al, 1989;England et al, 1994England et al, , 1996Amir et al, 1999).…”

Gabapentin Supplemented With Ropivacain Block of Trigger Points Improves Pain Control and Quality of Life in Trigeminal Neuralgia Patients When Compared With Gabapentin Alone

“…40 Complementary mechanisms associated with the local analgesic action of ROP and GBP may be at the basis for the strong pain reduction resulting from the association of both therapies in Protocol III. Low-dose ROP has an analgesic action similar to CBZ, because both drugs act on voltage-gated sodium channels, 11,43,44 reducing the membrane potential oscillations and membrane excitability associated to neuropathic pain 45 but not blocking nerve conduction. 15,44 GBP also suppresses ectopic afferent discharge activity generated by injured peripheral fibers, 10,46 without blocking nerve conduction.…”

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

“…It affects approximately 7% of the general population and is insufficiently treated with currently available drugs (1). Following nerve injury, there is ectopic spontaneous activity of afferent neurons due to the increased expression of voltage-gated sodium channels (Na v s) (2,3). This hyperexcitability mediates enduring changes in the nervous system, contributing to both peripheral and central sensitization (4).…”