Mechanism of dorsal root ganglion stimulation for pain relief in painful diabetic polyneuropathy is not dependent on GABA release in the dorsal horn of the spinal cord

Abstract

AimsIt is hypothesized that dorsal root ganglion stimulation (DRGS), sharing some of the mechanisms of traditional spinal cord stimulation (SCS) of the dorsal columns, induces γ‐aminobutyric acid (GABA) release from interneurons in the spinal dorsal horn.MethodsWe used quantitative immunohistochemical analysis in order to investigate the effect of DRGS on intensity of intracellular GABA‐staining levels in the L4‐L6 spinal dorsal horn of painful diabetic polyneuropathy (PDPN) animals. To establish the maximal pain relieving effect, we tested for mechanical hypersensitivity to von Frey filaments and animals received 30 minutes of DRGS at day 3 after implantation of the electrode. One day later, 4 Sham‐DRGS animals and four responders‐to‐DRGS received again 30 minutes of DRGS and were perfused at the peak of DRGS‐induced pain relief.ResultsNo significant difference in GABA‐immunoreactivity was observed between DRGS and Sham‐DRGS in lamina 1‐3 of the spinal levels L4‐6 neither ipsilaterally nor contralaterally.ConclusionsDorsal root ganglion stimulation does not induce GABA release from the spinal dorsal horn cells, suggesting that the mechanisms underlying DRGS in pain relief are different from those of conventional SCS. The modulation of a GABA‐mediated “Gate Control” in the DRG itself, functioning as a prime Gate of nociception, is suggested and discussed.

The Effect of Clinically Controllable Factors on Neural Activation During Dorsal Root Ganglion Stimulation

“…Previous animal studies of SCS demonstrated increased levels of γ‐amino butyric acid (GABA), an inhibitory neurotransmitter, in the spinal cord (71), and increased paw withdrawal thresholds in animals that responded to SCS (72) predominantly driven through the GABA B receptor (73, 74). However, a recent study in rats concluded that DRGS does not cause GABA release in the dorsal horn (75), indicating DRGS may provide pain relief through other mechanisms.…”

“…Koetsier and colleagues suggested that instead of driving GABAergic inhibition in the dorsal horn, DRGS may provide pain relief by inducing GABAergic inhibition through GABA signaling within the DRG (75). Du and colleagues concluded that in rats, activating small‐, medium‐, or large‐diameter DRG neurons can induce GABA release in the DRG, and that nearly all small‐diameter DRG neurons (putative nociceptors) can respond to GABA (76).…”

The Pathways and Processes Underlying Spinal Transmission of Low Back Pain: Observations From Dorsal Root Ganglion Stimulation Treatment

“…However, administration of GABA and glycine antagonists do not block inhibition by very low frequency (<20 Hz) stimulation (131, 132). A recent study demonstrated that DRG‐S does not induce GABA release in the DH (141). Thus, DRG‐S, especially at very low frequencies, is likely to be less dependent on GABAergic mechanisms.…”

Spinal cord stimulation in chronic neuropathic pain: mechanisms of action, new locations, new paradigms

“…Although a recent computational study indeed suggested that DRGS may inhibit nociception by activating pain-gating mechanisms in the dorsal horn through repeated activation of large myelinated (Aβ) afferents, 31 another study found that the pain-relieving effect of DRGS is not likely to be dependent on GABA release in the spinal dorsal horn at the L4-L6 lumbar level. 47 Some experimental studies suggest that, instead, DRGS suppresses excitability of neurons with predominantly slow-conducting nociceptive fibers (C fibers). 44 , 48 Because of the unique pseudounipolar design of DRG neurons, the DRG is likely to act as an impediment or low-pass filter to electrical impulses traveling from the peripheral nociceptor to the spinal cord in response to electrical stimulation (Fig.…”