Conventional Dorsal Root Ganglion Stimulation in an Experimental Model of Painful Diabetic Peripheral Neuropathy: A Quantitative Immunocytochemical Analysis of Intracellular γ-Aminobutyric Acid in Dorsal Root Ganglion Neurons

Abstract

Background and Objective The sensory cell somata in the DRG contain all equipment necessary for extensive GABAergic signaling and are able to release GABA upon depolarization. With this study, we hypothesize that pain relief induced by conventional dorsal root ganglion stimulation (Con‐DRGS) in animals with experimental painful diabetic peripheral neuropathy is related to the release of GABA from DRG neurons. With use of quantitative immunocytochemistry, we hypothesize DRGS to result in a decreased intensity of intracellular GABA‐immunostaining in DRG somata. Materials and Methods Female Sprague‐Dawley rats (n = 31) were injected with streptozotocin (STZ) in order to induce Diabetes Mellitus. Animals that developed neuropathic pain after four weeks (Von Frey) were implanted with a unilateral DRGS device at L4 (n = 14). Animals were then stimulated for 30 min with Con‐DRGS (20 Hz, pulse width = 0.2 msec, amplitude = 67% of motor threshold, n = 8) or Sham‐DRGS (n = 6), while pain behavior (von Frey) was measured. DRGs were then collected and immunostained for GABA, and a relation to size of sensory cell soma diameter (small: 12–26 μm, assumed to be C‐fiber related sensory neurons; medium: 26–40 μm, assumed to be Aδ related sensory neurons; and large: 40–54 μm, assumed to be Aβ related sensory neurons) was made. Results DRGS treated animals showed significant reductions in STZ‐induced mechanical hypersensitivity. No significant differences in GABA immunostaining intensity per sensory neuron cell soma type (small‐, medium‐, or large‐sized) were noted in DRGs of stimulated (Con‐DRGS) animals versus Sham animals. No differences in GABA immunostaining intensity per sensory cell soma type in ipsi‐ as compared to contralateral DRGs were observed. Conclusion Con‐DRGS does not affect the average intracellular GABA immunofluorescence staining intensity in DRG sensory neurons of those animals which showed significant pain reduction. Similarly, no soma size related changes in intracellular GABA immunofluorescence were observed following Con‐DRGS.

Electrical Stimulation Increases Axonal Growth from Dorsal Root Ganglia Co-Cultured with Schwann Cells in Highly Aligned PLA-PPy-Au Microfiber Substrates

“…Finally, the current was maintained in 0.5 mA and the frequency was lowered to 3 Hz (experiment #4), which gave rise to a positive effect on axonal growth, showing an increased axonal extension and axonal sprouting for the electrically stimulated DRG, compared with the non-stimulated ones. Several studies of neurostimulation of DRG have observed that low frequencies (<20 Hz) have a beneficial effect on pain relief, inducing the dorsal horn of the spinal cord inhibition via the activation of low threshold mechanoreceptors and the release of endorphins and dynorphins [ 76 , 77 , 78 , 79 ]. Therefore, we could say that the applied stimulation frequency of 3 Hz is within the physiological range of DRG activation.…”

Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Narirutin via Block of Nav1.7 Voltage-Gated Sodium Channel

“…Inspired by our calcium imaging results indicating that Narirutin presents disparate effects on four types of neurons, we hypothesis that Na v 1.7 expression in different types of neurons after SNI is varied. Since the small-diameter neurons are mainly C-fiber-related nociceptors [ 38 , 39 ], we conducted immunostaining CGRP and IB4 for labeling unmyelinated peptidergic or non-peptidergic sensory neurons, and NF200 for myelinated neurons [ 40 ]. Calcitonin gene-related peptide (CGRP), a 37 amino-acid neuropeptide found mostly in peptidergic sensory C-fibers, has been suggested to be implicated in the pathogenesis of neuropathic pain [ 41 ], which is likely mediated by modulating nociception and sustaining neurogenic inflammation that leads to further peripheral and central pain sensitization [ 42 ].…”

Implantable, Programmable, and Wireless Device for Electrical Stimulation of the Dorsal Root Ganglion in Freely-Moving Rats: A Proof of Concept Study

“… 3 , 4 There is evidence indicating that the DRG can be a relevant target for analgesic treatment in the experimental animal models. 5 , 6 More recent studies on the experimental model of painful diabetic peripheral neuropathy in rats confirmed a generally positive effect on animal pain-related behavior using conventional 7 , 8 and burst DRG stimulation. Furthermore, a similar effect was obtained for experimental animal models of osteoarthritis 10 and rheumatoid arthritis.…”

“…Experimental animal studies preceding clinical studies or performed in parallel with them can enhance the understanding of the effect of electrical stimulation on injured DRGs. However, a systematic review of the literature revealed only six publications that have analyzed DRG stimulation in experimental pain models 8 , 9 , 24–27 and two more that investigated the stimulation effect in healthy animals. 28 , 29 In all these cases, the pathophysiological mechanisms behind DRG stimulation still remain largely unknown.…”