Comparison of intensity-dependent inhibition of spinal wide-dynamic range neurons by dorsal column and peripheral nerve stimulation in a rat model of neuropathic pain

Abstract

Background: Spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS) are thought to reduce pain by activating a sufficient number of large myelinated (Aβ) fibres, which in turn initiate spinal segmental mechanisms of analgesia. However, the volume of neuronal activity and how this activity is associated with different treatment targets is unclear under neuropathic pain conditions.

Methods: We sought to delineate the intensity-dependent mechanisms of SCS and PNS analgesia by in vivo extracellular recordings from spinal wide-dynamic range neurons in nerve-injured rats. To mimic therapeutic SCS and PNS, we used bipolar needle electrodes and platinum hook electrodes to stimulate the dorsal column and the tibial nerve, respectively. Compound action potentials were recorded to calibrate the amplitude of conditioning stimulation required to activate A-fibres and thus titrate the volume of activation.

Results: Dorsal column stimulation (50 Hz, five intensities) inhibited the windup (a short form of neuronal sensitization) and the C-component response of wide-dynamic range neurons to graded intracutaneous electrical stimuli in an intensity-dependent manner. Tibial nerve stimulation (50 Hz, three intensities) also suppressed the windup in an intensity-dependent fashion but did not affect the acute C-component response.

Conclusions: SCS and PNS may offer similar inhibition of short-term neuronal sensitization. However, only SCS attenuates spinal transmission of acute noxious inputs under neuropathic pain conditions. Our findings begin to differentiate peripheral from spinal-targeted neuromodulation therapies and may help to select the best stimulation target and optimum therapeutic intensity for pain treatment.

Conflict of interest statement

Conflicts of interest

Drs. Yun Guan and Srinivasa N. Raja received research grant support from Medtronic, Inc. Paul W. Wacnik is employed by Medtronic, Inc. However, none of the authors has a commercial interest in the material presented in this paper. No other relationships might lead to a conflict of interest in the current study.

© 2014 European Pain Federation - EFIC®

Figures

Figure 1

Schematic diagram illustrating the experimental setup in rats that underwent an L5 spinal nerve ligation (SNL). (A) Left: The intensity of dorsal column stimulation was calibrated by recording the sciatic antidromic compound action potential (AP) evoked by bipolar electrical stimulation (0.01–3.0 mA, 0.2 ms) at the dorsal column (T13-L1 spinal level). Wide-dynamic range neuronal activity was recorded with a microelectrode inserted within the L4 spinal segment. Electrical test stimuli were applied to the skin receptive field of the dorsal horn neuron. Right: The intensities that produced the first detectable Aα/β waveform (Aβ-threshold or Ab0) and the peak Aα/β waveform (Aβ-plateau, or Ab1) were determined. (B) Left: The intensity of tibia nerve stimulation was calibrated by recording orthodromic compound APs at L4 dorsal root Right: The waves of compound APs corresponding to Aα/β- and Aδ-fibre activation in response to tibial stimulation. Ad0: The intensities that produced the first detectable Aδ waveform. (C) An analogue recording of the wide-dynamic range neuronal response to the first, eighth and 16th stimulus of a train of windup-inducing electrical stimuli (0.5 Hz, 16 pulses, 2.0 ms, supra-C-threshold) before (i.e., baseline) and 0–15 min after dorsal column stimulation of 0.5(Ab0 + Ab1) and Ab1 intensities (5 min, 0.2 ms).

Figure 2

Effects of dorsal column conditioning stimulation on wide-dynamic range (WDR) neuronal response in nerve-injured rats. (A) The windup function at 0–15 min after dorsal column stimulation, the time of peak inhibitory effect, is shown for each group [0.5Ab0: n = 18, Ab0: n = 19, 0.5(Ab0 + Ab1): n = 18, Ab1: n = 24, Ab2: n = 19]. The averaged prestimulation baseline was used for comparison. (B) The area under the windup function to a 0.5 Hz train was significantly decreased from the baseline at 0–15 min after dorsal column stimulation at intensities of 0.5(Ab0 + Ab1), Ab1 and Ab2. (C) The areas under the windup function to a 0.5 Hz train after dorsal column stimulation were normalized to the baseline value. (D) The stimulus-response functions of the C-component of WDR neurons evoked by graded electrical stimulation (0.1–10 mA, 2.0 ms) after dorsal column stimulation are shown. The averaged prestimulation baseline was used for comparison. (E) The area under the stimulus-response function was significantly decreased from baseline at 0–15 min after conditioning stimulation at intensities of 0.5(Ab0 + Ab1), Ab1 and Ab2. (F) The C-component after dorsal column stimulation was normalized to the respective prestimulation baseline value. (G) The C-threshold after dorsal column stimulation was also normalized to the respective baseline value. *p < 0.05, **p < 0.01, ***p < 0.001 versus baseline. Data are expressed as mean ± standard error of the mean. Error bars in A and D are omitted to improve the clarity.

Figure 3

Effects of tibial nerve stimulation on wide-dynamic range (WDR) neuronal response in nerve-injured rats. (A) Windup functions after tibial nerve stimulation are shown for different intensity groups (Ab0: n = 28, Ab1: n = 34, Ab2: n = 30). The averaged prestimulation windup function was used for comparison. (B) The area under the windup function to a 0.5 Hz train was significantly decreased from the baseline at 0–15 min after tibial nerve stimulation at intensities of Ab0, Ab1 and Ab2. (C) The area under the windup function to a 0.5 Hz train was normalized to the baseline value. (D) The stimulus-response functions of the C-component to graded electrical stimulation (0.1–10 mA, 2.0 ms) before and after tibial nerve stimulation. The averaged prestimulation baseline was used for comparison. (E) The C-component was not significantly changed after tibial nerve stimulation. (F) The C-component after tibial nerve stimulation was normalized to the respective prestimulation baseline value. *p < 0.05, **p < 0.01, ***p < 0.001 versus baseline. Data are expressed as mean ± standard error of the mean. Error bars in A and D are omitted to improve the clarity.

Figure 4

Comparison of the peak inhibitory effects between dorsal column stimulation and tibial nerve stimulation. (A) The decrease in the area under the windup function to a 0.5 Hz train after dorsal column stimulation at Ab0, Ab1 and Ab2 intensities was not significantly different from that after tibial nerve stimulation. (B) Compared with tibial nerve stimulation, dorsal column stimulation induced a significantly greater inhibition of the C-component to graded intracutaneous electrical stimuli (0.1–10 mA, 2 ms) at Ab1 and Ab2 intensities. **p < 0.01, ***p < 0.001 versus prestimulation baseline, ##p < 0.01, ###p < 0.001 versus tibial nerve stimulation. Data are expressed as mean + standard error of the mean.