Dorsal Root Ganglion Stimulation for Chronic Pain: Hypothesized Mechanisms of Action

Abstract

Dorsal root ganglion stimulation (DRGS) is a neuromodulation therapy for chronic pain that is refractory to conventional medical management. Currently, the mechanisms of action of DRGS-induced pain relief are unknown, precluding both our understanding of why DRGS fails to provide pain relief to some patients and the design of neurostimulation technologies that directly target these mechanisms to maximize pain relief in all patients. Due to the heterogeneity of sensory neurons in the dorsal root ganglion (DRG), the analgesic mechanisms could be attributed to the modulation of one or many cell types within the DRG and the numerous brain regions that process sensory information. Here, we summarize the leading hypotheses of the mechanisms of DRGS-induced analgesia, and propose areas of future study that will be vital to improving the clinical implementation of DRGS. PERSPECTIVE: This article synthesizes the evidence supporting the current hypotheses of the mechanisms of action of DRGS for chronic pain and suggests avenues for future interdisciplinary research which will be critical to fully elucidate the analgesic mechanisms of the therapy.

Keywords: Dorsal root ganglion stimulation; chronic pain; electric stimulation; implanted neurostimulators; neuropathic pain.

Figure 1:

DRGS and surrounding anatomy. A) Axial view of a human spinal column with a DRGS electrode array in place. B) Sagittal view of a DRGS electrode array in the foramen. C) Histology image of a human lumbar DRG stained for 200 kDa neurofilament. Axons appear as miniscule dots; cell bodies appear as larger dark spots. D) Sensory neuron types in the DRG and their projections into the spinal cord. The first five lamina of the dorsal horn are labeled to indicate where different sensory neuron types send axon collaterals.

Figure 2:

DRGS may drive pain-gating mechanisms in the spinal cord dorsal horn, the DRG, or both. DRGS applies trains of electrical pulses which induce APs in Aβ-neurons, which activate inhibitory interneurons in lamina ii_i and iii in the dorsal horn. Concurrently, Aβ-neurons may release GABA within the DRG, which can act on C-neurons and potentially prevent ectopic APs from propagating to the spinal cord.

Figure 3:

DRGS may augment the low-pass filtering properties of nociceptive C-neurons. A) Ectopic APs indicative of spontaneous pain propagate along the peripheral axons of C-neurons towards the central nervous system. B) The DRGS pulse train induces APs in or near C-neuron somata causing calcium influx through voltage-gated calcium channels, putatively triggering potassium efflux through calcium-activated SK channels. C) Potassium efflux hyperpolarizes the soma, which electrotonically hyperpolarizes the T-junction. D) Orthodromically propagating APs are unable to propagate passed the hyperpolarized T-junction into the spinal axon.