Burst and Tonic Spinal Cord Stimulation Differentially Activate GABAergic Mechanisms to Attenuate Pain in a Rat Model of Cervical Radiculopathy.

OBJECTIVE: Spinal cord stimulation (SCS) is widely used to treat neuropathic pain. Burst SCS, an alternative mode of stimulation, reduces neuropathic pain without paresthesia. However, the effects and mechanisms of burst SCS have not been compared to conventional tonic SCS in controlled investigations. This study compares the attenuation of spinal neuronal activity and tactile allodynia, and the role of γ-aminobutyric acid (GABA) signaling during burst or tonic SCS in a rat model of cervical radiculopathy. METHODS: The effects of burst and tonic SCS were compared by recording neuronal firing before and after each mode of stimulation at day 7 following a painful cervical nerve root compression. Neuronal firing was also recorded before and after burst and tonic SCS in the presence of the GABAB receptor antagonist, CGP35348. RESULTS: Burst and tonic SCS both reduce neuronal firing. The effect of tonic SCS, but not burst SCS, is blocked by CGP35348. In a separate study, spinal cord stimulators were implanted to deliver burst or tonic SCS beginning on day 4 after painful nerve root compression; allodynia and serum GABA concentration were measured through day 14. Burst and tonic SCS both reduce allodynia. Tonic SCS attenuates injury-induced decreases in serum GABA, but GABA remains decreased from baseline during burst SCS. CONCLUSION AND SIGNIFICANCE: Together, these studies suggest that burst SCS does not act via spinal GABAergic mechanisms, despite its attenuation of spinal hyperexcitability and allodynia similar to that of tonic SCS; understanding other potential spinal inhibitory mechanisms may lead to enhanced analgesia during burst stimulation.

Stimulation parameters define the effectiveness of burst spinal cord stimulation in a rat model of neuropathic pain.

INTRODUCTION: Although burst spinal cord stimulation (SCS) has been reported to reduce neuropathic pain, no study has explicitly investigated how the different parameters that define burst SCS may modulate its efficacy. The effectiveness of burst SCS to reduce neuronal responses to noxious stimuli by altering stimulation parameters was evaluated in a rat model of cervical radiculopathy. METHODS: Neuronal firing was recorded in the spinal dorsal horn before and after burst SCS on day 7 following painful cervical nerve root compression (N = 8 rats). The parameters defining the stimulation (number of pulses per burst, pulse frequency, pulse width, burst frequency, amplitude) were individually varied in separate stimulation trials while holding the remaining parameters constant. The percent reduction of firing of wide-dynamic-range (WDR) and high-threshold neurons after SCS and the percentage of neurons responding to SCS were quantified for each parameter and correlated to the charge per burst delivered during stimulation. RESULTS: Pulse number, pulse width, and amplitude each were significantly correlated (p <0.009) to suppression of neuronal firing after SCS. Pulse frequency and amplitude significantly affected (p <0.05) the percentage of responsive neurons. Charge per burst was correlated to a reduction of WDR neuronal firing (p <0.03) and had a nonlinear effect on the percentage of neurons responding to burst SCS. CONCLUSIONS: Burst SCS can be optimized by adjusting relevant stimulation parameters to modulate the charge delivered to the spinal cord during stimulation. The efficacy of burst SCS is dependent on the charge per burst.

Upper thoracic postsynaptic dorsal column neurons conduct cardiac mechanoreceptive information, but not cardiac chemical nociception in rats.

Postsynaptic dorsal column (PSDC) neurons transmit noxious visceral information from the lower thoracic and lumbosacral spinal cord. Cuneothalamic neurons in the PSDC pathway and upper thoracic (T(3)-T(4)) spinal neurons ascending through the ventrolateral funiculus (VLF) have been shown to transmit nociceptive cardiac information. Therefore, we hypothesized that upper thoracic PSDC neurons transmit noxious cardiac information. Neuronal responses to intrapericardially injected mechanical (1.0 ml saline) and noxious chemical (0.2 ml algogenic chemicals) stimuli were recorded from antidromically activated PSDC and VLF neurons in the T(3)-T(4) spinal cord of anesthetized Sprague-Dawley rats. Of the PSDC neurons, 43% responded to mechanical stimulation, but only one responded to noxious chemical stimuli. Fifty-eight percent of VLF neurons responded to mechanical stimulation and all responded to noxious chemical stimulation. Fluoro-Ruby (FR)-labeled PSDC neurons in the T(3)-T(4) spinal cord of Sprague-Dawley rats were processed for c-fos immunohistochemistry following intrapericardial stimulation with mechanical, chemical, or control stimuli. Sections were viewed under epifluorescence and light microscopy to detect FR-labeled neurons containing a c-fos immunoreactive (IR) nucleus. An average of 6 PSDC neurons per rat was found in the T(3) and T(4) spinal segments. The average number of c-fos-IR neurons per segment varied by type of stimulus: 12 (control), 67 (chemical) and 85 (mechanical) for T(3) and 8 (control), 37 (chemical) and 62 (mechanical) for T(4). None of the 200 PSDC neurons examined expressed c-fos-IR regardless of stimulus. Together, these results suggest that thoracic PSDC neurons transmit mechanical cardiac information, but they play a minimal role in cardiac nociception.