Modulators of Calcium Influx Regulate Membrane Excitability in Rat Dorsal Root Ganglion Neurons

Abstract

Background Chronic neuropathic pain resulting from neuronal damage remains difficult to treat, in part due to incomplete understanding of underlying cellular mechanisms. We have previously shown that inward Ca2+ flux (ICa) across the sensory neuron plasmalemma is decreased in a rodent model of chronic neuropathic pain, but the direct consequence of this loss of ICa on function of the sensory neuron has not been defined. We therefore examined the extent to which altered membrane properties after nerve injury, especially increased excitability that may contribute to chronic pain, are attributable to diminished Ca2+ entry. Methods Intracellular microelectrode measurements were obtained from A-type neurons of dorsal root ganglia excised from control rats and those with neuropathic pain behavior following spinal nerve ligation. Recording conditions were varied to suppress or promote ICa while biophysical parameters and excitability were determined. Results Both lowered external bath Ca2+ concentration and blockade of ICa with bath cadmium diminished the duration and area of the afterhyperpolarization (AHP), accompanied by decreased current threshold for action potential (AP) initiation and increased repetitive firing during sustained depolarization. Reciprocally, elevated bath Ca2+ increased the AHP and suppressed repetitive firing. Voltage sag during neuronal hyperpolarization, indicative of the cation-nonselective H-current, diminished with lowered bath Ca2+, cadmium application, or chelation of intracellular Ca2+. Additional recordings with selective blockers of ICa subtypes showed that N-, P/Q, L-, and R-type currents each contribute to generation of the AHP, and that blockade of any of these as well as the T-type current slows the AP upstroke, prolongs the AP duration, and (except for L-type current) decreases the current threshold for AP initiation. Conclusions Taken together, our findings show that suppression of ICa decreases the AHP, reduces the hyperpolarization-induced voltage sag, and increases excitability in sensory neurons, replicating changes that follow peripheral nerve trauma. This suggests that the loss of ICa previously demonstrated in injured sensory neurons contributes to their dysfunction and hyperexcitability, and may lead to neuropathic pain. Implications Statement Loss of inward Ca2+ current in A-type neurons, such as follows peripheral nerve injury, contributes to increased sensory neuron excitability. Measures that increase inward Ca2+ flux may potentially be therapeutic for painful peripheral neuropathy.

Insufficiency of Cellular Energy (ICE) May Precede Neurodegeneration in Alzheimer’s Disease and Be Treatable via the Alternative Cellular Energy (ACE) Pathway

“…Thus, a lessening of the membrane potential, for example from −70 mV to −60 mV, will lead to depolarization in response to minor stimuli that are unable to trigger cells with a normal membrane potential. Indeed, a lowered differential electrical charge is an early characteristic of neuronal cell damage [31] and by inference neuronal hyperactivity may be expected as an early manifestation of ICE.…”

Dynamic interplay of excitatory and inhibitory coupling modes of neuronal L-type calcium channels

“…Later, it was found that LTCCs can also induce afterdepolarizations (ADPs), e.g., by activation of a neuronal Ca 2ϩ -dependent nonspecific cation (CAN) current (30). This divergent coupling has since been confirmed in various neuronal populations, and its role is still the focus of current research (23,25,28). Hence, LTCCs may regulate neuronal excitability in opposing manners, depending on the prevalence of coupling to potassium or cation channels.…”

Sigma-1 Receptor Antagonism Restores Injury-Induced Decrease of Voltage-Gated Ca2+ Current in Sensory Neurons

“…BL, baseline. a different result is expected in the periphery, where I Ca is required for natural suppression of repetitive firing via opening of Ca 21 -activated K 1 channels, and for filtering of high-frequency pulse trains at the sensory neuron T-junction in the DRG Lirk et al, 2008). We have identified loss of I Ca in sensory neuron somata as a reliable consequence of painful nerve injury (Hogan et al, 2000;McCallum et al, 2006McCallum et al, , 2011 that, like s1R activation, acts through all VGCC subtypes.…”

“…Following nerve trauma, I Ca is reduced in DRG neurons (Hogan et al, 2000;McCallum et al, 2006), which leads to decreased activation of Ca 21 -activated K 1 currents. The resulting loss in afterhyperpolarization and reduced membrane input resistance lead to hyperexcitability of primary afferent fibers and enhanced pain (Sapunar et al, 2005;Lirk et al, 2008). The analgesic agents gabapentin and pregabalin, commonly used for neuropathic pain, also inhibit I Ca (Hendrich et al, 2008;Patel et al, 2013), resulting in an apparent paradox.…”