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.

Comparison of burst and tonic spinal cord stimulation on spinal neural processing in an animal model.

OBJECTIVES: Spinal cord stimulation (SCS) using bursts of pulses suppressed neuropathic pain as well or better than tonic stimulation and limited the incidences of parasthesias. The present translational study explored possible differences in mechanisms of burst and tonic SCS on nociceptive spinal networks and/or the gracile nucleus supraspinal relay. MATERIALS AND METHODS: Visceromotor reflexes (VMRs, a nociceptive response) or extracellular activity of either L6-S2 spinal neurons or gracile nucleus neurons were recorded during noxious somatic stimulation (pinching) and visceral stimulation (colorectal distension [CRD]) in anesthetized rats. A stimulating (unipolar, ball) electrode at L2-L3 delivered 40 Hz burst or tonic SCS at different intensities relative to motor threshold (MT). RESULTS: Average MTs for burst SCS were significantly lower than for tonic SCS. Burst SCS reduced the VMR more than tonic SCS. After high-intensity SCS (90% MT), spinal neuronal responses to CRD and pinch were reduced similarly for burst and tonic SCS. At low-intensity SCS (60% MT), only burst SCS significantly decreased the nociceptive somatic response. Tonic but not burst SCS significantly increased spontaneous activity of neurons in the gracile nucleus. CONCLUSION: Based on the clinically relevant burst versus tonic parameters used in this study, burst SCS is more efficacious than tonic SCS in attenuating visceral nociception. Burst and tonic SCS also suppress lumbosacral neuronal responses to noxious somatic and visceral stimuli; however, burst SCS has a greater inhibitory effect on the neuronal response to noxious somatic stimuli than to noxious visceral stimuli. Reduced or abolished paresthesia in patients may be due in part to burst SCS not increasing spontaneous activity of neurons in the gracile nucleus.

Is constant current or constant voltage spinal cord stimulation superior for the suppression of nociceptive visceral and somatic stimuli? A rat model.

OBJECTIVES: This study compares the effects of constant current (CC) and constant voltage (CV) spinal cord stimulation (SCS) at various frequencies and intensities on standard nociceptive measurements in rats, the visceromotor reflex (VMR) and neuronal activity, during noxious visceral and somatic stimuli. MATERIALS AND METHODS: Abdominal muscle electromyographic activity changes were measured to indicate VMR, and extracellular activity of L6-S2 spinal neurons was recorded during somatic (pinching) and noxious visceral stimulation (colorectal distension [CRD], 60 mmHg) in anesthetized rats. A stimulating (unipolar ball) electrode at L2-L3 delivered CC- or CV-SCS at varied frequencies and intensities. RESULTS: CC-SCS reduced VMR evoked by CRD significantly more than CV-SCS (p < 0.05). For neuronal activity, high-frequency CC-SCS (40 and 100 Hz) and CV-SCS (100 Hz) effectively reduced intraspinal somatic nociceptive transmission more than low-frequency SCS (2 Hz). No significant differences were observed between the effects of CC- and CV-SCS on spontaneous activity and nociceptive responses of spinal neurons to noxious CRD following short- (five to ten minutes) or long-term (20-30 min) SCS. CONCLUSIONS: Although high-frequency CC- and CV-SCS may be more useful for the management of somatic pain, CC-SCS may be more effective for treating complex pain systems like visceral hypersensitivity.

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.