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ANALGESIA

Restoration of Calcium Influx Corrects Membrane Hyperexcitability in Injured Rat Dorsal Root Ganglion Neurons

Quinn Hogan, MD^*, Philipp Lirk, MD^*, Mark Poroli, BS^*, Marcel Rigaud, MD^*, Andreas Fuchs, MD^*, Patrick Fillip, MD^*, Marko Ljubkovic, MD^*||, Geza Gemes, MD^*, and Damir Sapunar, MD, PhD^*||

From the *Department of Anesthesiology, Medical College of Wisconsin, Milwaukee Veterans Administration Medical Center, Milwaukee, Wisconsin; Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Innsbruck, Austria; Department of Intensive Care and Anesthesiology, Medical University of Graz, Graz, Austria; and ||University of Split Medical School, Split, Croatia.

Address correspondence and reprint requests to Quinn Hogan, MD, Department of Anesthesiology, MEB, Department of Anesthesiology, 8701 Watertown Plank Rd, Milwaukee, WI 53226. Address e-mail to qhogan{at}mcw.edu.

Abstract

BACKGROUND: We have previously shown that a decrease of inward Ca²⁺ flux (I_Ca) across the sensory neuron plasmalemma, such as happens after axotomy, increases neuronal excitability. From this, we predicted that increasing I_Ca in injured neurons should correct their hyperexcitability.

METHODS: The influence of increased or decreased I_Ca upon membrane biophysical variables and excitability was determined during recording from A-type neurons in nondissociated dorsal root ganglia after spinal nerve ligation using an intracellular recording technique.

RESULTS: When the bath Ca²⁺ level was increased to promote I_Ca, the after-hyperpolarization was decreased and repetitive firing was suppressed, which also followed amplification of Ca²⁺-activated K⁺ current with selective agents NS1619 and NS309. A decreased external bath Ca²⁺ concentration had the opposite effects, similar to previous observations in uninjured neurons.

CONCLUSIONS: These findings indicate that at least a part of the hyperexcitability of somatic sensory neurons after axotomy is attributable to diminished inward Ca²⁺ flux, and that measures to restore I_Ca may potentially be therapeutic for painful peripheral neuropathy.

Various laboratories, including our own, have observed a decreased inward Ca²⁺ flux (I_Ca) in axotomized somatic sensory neurons,1–5 which are also noted to be hyperexcitable.6,7 We have recently shown that suppression of I_Ca in uninjured neurons produces changes that simulate axotomy, including a diminished duration and area of the after-hyperpolarization (AHP), a decreased current threshold for action potential (AP) initiation, and increased repetitive firing during sustained depolarization.8 From these observations, we speculate that depressing I_Ca should have less effect on injured sensory neurons in which prior loss of I_Ca would preclude this action. More importantly, these findings also predict that increasing I_Ca in injured sensory neurons will correct their aberrant hyperexcitability, which would have translational importance. Accordingly, we have tested the effects of manipulating I_Ca in sensory neurons from animals made hyperalgesic by peripheral nerve injury. Since activation of Ca²⁺-dependent K⁺ current (I_K(Ca)) is a critical downstream mechanism through which I_Ca regulates neuronal excitability,9–12 we additionally tested the response of injured neurons to agents that selectively increase I_K(Ca) through increasing the Ca²⁺ sensitivity of specific channel subtypes.

METHODS

All procedures used in the study were approved by the Animal Resource Center of the Medical College of Wisconsin.

Animal Preparation
During isoflurane anesthesia (2% in oxygen), spinal nerve ligation (SNL) was performed on male Sprague-Dawley rats (200–300 g) at the fifth lumbar (L5) and L6 levels with 6-0 silk ligature and distal transection, which was confirmed at the time of tissue harvest. Unlike the originally described method,13 paraspinous muscles and the adjacent articular process were not removed.

Behavioral Testing
Sensory responsiveness was tested using a method that we have validated for selective identification of neuropathic hyperalgesia.14 On three separate days in the second and third postoperative weeks, the plantar surface of each hind foot was touched 10 times with a 22-gauge spinal anesthesia needle with pressure adequate to indent but not penetrate the skin. Tissue was harvested only from animals that displayed a hyperalgesia-type response with sustained paw lifting, shaking or licking (70% of the injured animals). Such a response is absent from control animals.

Tissue Preparation and Electrophysiological Recording
Our methods were similar to those described previously.8 Briefly, ganglia were removed 20 ± 3 days after surgery, a time at which hyperalgesia has fully developed.14 During anesthesia, the L5 dorsal root ganglion (DRG) and attached dorsal roots were removed. After removal of the capsule, the DRG was secured in a recording chamber and perfused with 35°C artificial cerebrospinal fluid (aCSF: NaCl 128 mM, KCl 3.5 mM, MgCl₂ 1.2 mM, CaCl₂ 2.3 mM, NaH₂PO₄ 1.2 mM, NaHCO₃ 24.0 mM, glucose 11.0 mM) aerated by 5% CO₂ and 95% O₂ to maintain a pH of 7.35. The dorsal roots were placed on stimulating electrodes for generation of conducted APs. DRG somata were impaled with microelectrodes filled with 2 M potassium acetate (80–120 M) during microscopy using differential interference contrast optics and infrared illumination. Membrane potential was recorded using either an active bridge amplifier, or discontinuous current clamp recording mode (2 kHz switching; Axoclamp 2B, Axon Instruments, Foster City, CA) when voltage was recorded during current injection through the recording pipette. Data were digitized at 10 kHz (discontinuous) or 20 kHz data acquisition and analysis (bridge; Digidata 1322A and Axograph 4.9, Axon Instruments).

APs measures (Fig. 1) included AP and AHP durations and the area under the curve for the AHP (AHParea), and slope of the ascending limb (dV/dt) determined from the differentiated trace. Input resistance was calculated from the hyperpolarization during 100 ms current injection (0.5 nA).15 Voltage "sag" in response to hyperpolarization, attributable to the H-current,16 was quantified as the fractional return from the peak hyperpolarization during 100 ms of 1.2 nA hyperpolarization current injection. Rheobase was determined as the minimum current able to elicit an AP during incremental injection of depolarizing current (0.5–10 nA for 100 mS) directly to the soma through the recording electrode. The pattern of impulse generation was determined during depolarizing current steps beyond rheobase, at which neurons either continued to produce single APs or fired repetitively. The influence of bath Ca²⁺ level or drug upon AP firing pattern was measured at a depolarizing voltage that first produced a bath Ca²⁺- or drug-induced difference in the number of APs generated.

View larger version (18K): [in this window] [in a new window]   Figure 1. Measurements determined from action potential (AP) trace. RMP, resting membrane potential; APamp., amplitude of AP; AP95%, duration of AP at 95% of amplitude; t, latency following axonal stimulation; AHPamp., amplitude of after-hyperpolarization; AHP80%, duration of afterhyperpolarization until 80% recovery to baseline.

Neurons were classified by conduction velocity (CV) calculated from conducted distance and latency. Adequately stable C-type neuron (CV <1.5 m/s) recordings were too few to report. Neurons with CV >15 m/s were considered A/β-type, and neurons with CV >1.5 m/s but CV <10 m/s were considered A-type. For neurons with CV between 10 and 15 m/S, long AP duration was used to categorize the cells as A-types.15

Ca²⁺ Current Modulation
To test whether injury precludes responses to decreased I_Ca, we examined the effects of decreasing the bath Ca²⁺ on L5 neurons after SNL (n = 14 A/β and 12 A). After baseline electrophysiologic variables were measured in aCSF, ganglia were exposed by bath change to an identical external solution except for a lower Ca²⁺ concentration achieved by substituting CaCl₂ with MgCl₂, producing a measured Ca²⁺ concentration of 0.35 mM. This reduces I_Ca to only 6% of baseline.8 Magnesium was added to a final concentration of 3.5 mM to exclude the possible influence of changed surface charge,17 and to maintain a constant divalent cation effect on potassium channels.18 To test whether augmenting I_Ca reverses the effects of injury, SNL L5 neurons (n = 24 A/β and 21 A) were exposed to a bath Ca²⁺ level of 7 mM. This solution increases I_Ca by 35%.8 The effects were measured after a wash-in interval of 3 min.

To explore the mechanism of the action of increasing I_Ca, we sought out repetitively firing neurons to expose to the I_K(Ca) activators NS1619 (10 µM), which selectively increases current through the large conductance (BK) channel,19,20 or NS309 (5 µM), which increases current through the small conductance (SK) and intermediate conductance (IK) channel subtypes.21,22 These were delivered by a microperfusion technique from a pipette with a 10-µM diameter tip that was positioned 200 µm from the impaled neuron, and ejected continuously by pressure applied to the back end of the pipette (Picospritzer II, General Valve Corp., Fairfield, NJ). Preliminary experiments indicated an effective five-fold dilution of pipette solution into the bath at the cell surface, so pipette concentrations of 50 µM for NS1619 and 25 µM NS309 were used.

All agents were purchased from Sigma-Aldrich Co. (St. Louis, MO).

Data Analysis and Statistics
Data are expressed as means ± sd. The effect of bath changes was evaluated using paired Student’s t-test to identify of significant drug effects in the context of natural variability between neurons under baseline conditions. Significance was accepted at P < 0.05.

RESULTS

Effects of Injury
SNL rats from which tissue was harvested showed a greater frequency of hyperalgesia-type responses ipsilateral to the injury (34% ± 6%; n = 37) than a contemporaneous control group of animals that had only a midline lumbar skin incision and staple closure (1% ± 1%; n = 68, P < 0.001).

Although this study was not designed to determine the effects of injury on electrophysiological variables, we note that, in comparison to a previously reported control group that was studied concurrently with the experiments reported here,8 axotomized L5 neurons after SNL developed electrophysiological changes consistent with those shown in previous examination of the effects of injury,6 including decreased AP amplitude and upstroke velocity, increased AP duration, and decreased AHP.

Decreasing I_Ca in Injured Neurons
We predicted that the injury-related loss of I_Ca should preclude the effects of further decreasing I_Ca by bath Ca²⁺ withdrawal in axotomized neurons. In fact (Table 1), low bath Ca²⁺ produced significant decreases in AHP dimensions and in rheobase that resembled changes seen in uninjured neurons8 and exceeded them in magnitude. Decreasing bath Ca²⁺ also decreased AP amplitude in axotomized A/β neurons, but not in A neurons, and inflection disappeared in 3 of 8 neurons, which is also similar to the effect observed in control neurons. A tendency for increased firing during depolarization was demonstrated, as five neurons showed increased firing, 18 were unchanged, and 1 fired less. Unlike control neurons, axotomized neurons showed no decrement in hyperpolarization-induced voltage sag during Ca²⁺ withdrawal in both A/β and A neurons.

View larger version (11K): [in this window] [in a new window]   Figure 2. Influence of increasing bath Ca2+ concentration on an axotomized A/β neuron. An increase of bath Ca2+ concentration from 2.3 to 7 mM increased the amplitude and area of the after-hyperpolarization (*, blue trace).

View larger version (17K): [in this window] [in a new window]   Figure 3. Increased bath Ca2+ concentration diminishes repetitive firing during depolarization of an axotomized A/β sensory neuron. A, Under baseline conditions of 2.3 mm bath Ca2+ concentration, depolarizing current injection produces an initial single action potential, and further depolarization results in repetitive firing. B, Under high bath Ca2+ conditions (7 mM), current injection results initially in no action potential and subsequently only a single action potential using comparable depolarization steps (C) as in A.

Increasing I_K(Ca) in Injured Neurons
Both I_K(Ca) enhancers NS309 and NS1619 produced effects that resembled exposure to high bath Ca²⁺ and reversed changes that follow injury (Table 2). Specifically, stimulation of SK and IK-type Ca²⁺-activated K⁺ channels with NS309 increased the rheobase, expanded the AHP, and caused all 7 repetitively firing neurons (4 A/β, 3 A) to fire less during depolarization (3.29 ± 1.60APs at baseline, 1.14 ± 0.38APs during NS309, P < 0.01; Fig. 4). Stimulation of BK-type Ca²⁺-activated K⁺ current with NS1619 also increased the rheobase, but did not increase AHP dimensions, consistent with its action on the earliest part of the repolarization phase.12 Like exposure to high bath Ca²⁺, NS1619 decreased the number of APs during neuron depolarization in all 8 repetitively firing neurons (6 A/β, 2 A; 3.50 ± 2.10 APs at baseline, 1.63 ± 0.92 APs during NS1619, P < 0.01).

View larger version (16K): [in this window] [in a new window]   Figure 4. NS309 (10 µm), which enhances Ca2+-activated K+ currents, reduces excitability in an axotomized A/β sensory neuron (different from the neuron in Fig. 3), similar to the action of high bath Ca2+. A, Under baseline conditions, depolarizing current injection produces repetitive firing (red trace). B, During application of NS309, current injection results in only a single action potential (red) during comparable depolarization steps (C) as in A. In both panels, a subthreshold current injection step induces an abortive depolarization that fails to produce a full action potential (green trace).

DISCUSSION

Our present results show that an increase of extracellular Ca²⁺, which increases I_Ca, reverses electrophysiological changes in sensory neurons that follow peripheral nerve trauma. Specifically, we have previously observed6 that axotomy by SNL decreases the AHP area by 51% (A/β) to 75% (A), and we now note that an increased bath Ca²⁺ concentration increases the AHP area of axotomized neurons by 19% (A/β) and 37% (A). Similarly, injury decreases rheobase by 28% (A/β) to 50% (A), whereas elevated bath Ca²⁺ increases the rheobase of injured neurons by 29% (A/β) and 27% (A). We as well as others1–5 have previously shown that axotomy diminishes I_Ca in primary sensory neurons, and thus the present observations support a role for this I_Ca loss in generating posttraumatic hyperexcitability.

In contrast with our expectations, axotomized L5 neurons after SNL still respond to depression of I_Ca with elevated indices of excitability, including a decreased current necessary for AP initiation (rheobase), decreased AHP dimensions, and an associated increased propensity for repetitive firing. This may be explained by a heightened sensitivity to further loss of I_Ca due to the already deficient I_Ca due to injury. This is supported by a prior study of dissociated sensory neurons in which hyperexcitability developed in axotomized neurons when intracellular Ca²⁺ levels were buffered at a low level, whereas this did not occur with control neurons.24

Calcium that enters through neuronal plasmalemmal Ca²⁺ channels has numerous regulatory functions, including the modulation of firing patterns by activation of I_K(Ca) and generation of the AHP. We previously demonstrated that rat DRG neurons express I_K(Ca) currents sensitive to blockers of BK, IK, and SK types of I_K(Ca).25 In the present experiments, we tested the role of I_K(Ca) as a downstream effector by which increased inward Ca²⁺ flux may depress excitability, using agents that directly enhance current through these channels. The results were similar to increasing I_Ca, including enhanced AHP and diminished repetitive firing. Also, similar to the effect of increased I_Ca during increased bath Ca²⁺, directly enhancing I_K(Ca) increases rheobase, which indicates a decreased neuronal tendency to trigger an initial AP. This effect is possibly due to the enhanced I_K(Ca) competing with the inward depolarizing currents during the nascent initial phase of AP generation (Fig. 4). We cannot exclude pathways other than increased activation of I_K(Ca) by which increasing I_Ca may modulate neuronal excitability. For instance, depressed neuronal Ca²⁺ levels permit transmission of higher frequency bursts of APs through the DRG than under conditions of normal Ca²⁺ levels.26 Also, various phosphatases and kinases are sensitive to intracellular Ca²⁺. One possibly important example is calcium/calmodulin-dependent protein kinase II, which acts on diverse cellular substrates that regulate neuronal excitability, including voltage-gated K⁺ channels,27 store-operated Ca²⁺ channels that replenish intracellular Ca²⁺ stores,28 and voltage-gated Ca²⁺ channels themselves.29

Our previous observations indicate that axotomy is associated with both diminished I_Ca1–3 and a loss of recruitable Ca²⁺-activated K⁺ channels25 in sensory neurons. The findings in the present study indicate that aberrant function of injured sensory neurons may be returned towards normal by increasing I_Ca, which may act through amplification of I_K(Ca). These findings imply that measures designed to increase inward Ca²⁺ flux or outward Ca²⁺-activated K⁺ flux in sensory neurons may provide analgesia after peripheral nerve trauma. This view is supported by evidence that spinal intrathecal Ca²⁺ administration is analgesic in animal models of acute somatic and visceral pain.30 However, other animal studies31,32 and clinical trials33,34 demonstrate that peptide blockers of voltage-gated Ca²⁺ channels administered intrathecally produce analgesia. The role of I_Ca varies in different nervous tissue and, unlike in the DRG, a dominant function of I_Ca in the spinal cord is neurotransmitter release. Thus, the excitatory effect of diminished I_Ca is a feature specifically of the peripheral elements of DRG neurons, and therapeutic application of increased I_Ca would need to be restricted anatomically to the DRG and away from the cord. We anticipate that rapidly advancing molecular technology may be one path to achieve this goal.

Footnotes

Accepted for publication April 4, 2008.

Supported by grant NS-42150 from the National Institutes of Health, Bethesda, MD, USA (to Q.H.).

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hogan, Q. Articles by Sapunar, D. Search for Related Content PubMed PubMed Citation Articles by Hogan, Q. Articles by Sapunar, D. Related Collections Mechanisms Pain Mechanisms Pain