Nonlinear Relation Between Burst Dorsal Root Ganglion Stimulation Amplitude and Behavioral Outcome in an Experimental Model of Painful Diabetic Peripheral Neuropathy

Abstract

Background and objective Dorsal root ganglion stimulation (DRGS) has recently emerged as a neuromodulation modality in the treatment of chronic neuropathic pain. The objective of this study was to compare the efficacy of different Burst‐DRGS amplitudes in an experimental model of painful diabetic peripheral neuropathy (PDPN). Methods Diabetes mellitus was induced in female Sprague–Dawley rats by intraperitoneal injection of streptozotocin (STZ, n = 28). Animals were tested for mechanical hypersensitivity (von Frey paw withdrawal test) before, and four weeks after STZ injection. PDPN rats (n = 13) were implanted with a unilateral bipolar electrode at the L5 DRG. Animals received Burst‐DRGS at 0%, 10%, 33%, 50%, 66%, and 80% of motor threshold (MT) in a randomized crossover design on post‐implantation days 2–7 (n = 9). Mechanical hypersensitivity was assessed before stimulation onset, 15 and 30 min during stimulation, and 15 and 30 min after stimulation. Results Burst‐DRGS at amplitudes of 33%, 50%, 66%, and 80% MT resulted in significant attenuation of STZ‐induced mechanical hypersensitivity at 15 and 30 min during stimulation, as well as 15 min after cessation of stimulation. No effect on mechanical hypersensitivity was observed for Burst‐DRGS at 0% MT and 10% MT. Optimal pain relief and highest responder rates were achieved with Burst‐DRGS at 50–66% MT, with an estimated optimum at 52% MT. Conclusion Our findings indicate a nonlinear relationship between Burst‐DRGS amplitude and behavioral outcome, with an estimated optimal amplitude of 52% MT. Further optimization and analysis of DRGS driven by insights into the underlying mechanisms related to the various stimulation paradigms is warranted.

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

“…At the same time, animals did show marked reductions in STZ‐induced mechanical hypersensitivity values after 30 min of stimulation. These reductions in pain behavior are comparable to those obtained previously in the same diabetic rat model ( 21 , 31 , 32 , 39 ), as well as in rat models of tibial nerve injury ( 25 , 27 ), collagen‐induced rheumatoid arthritis ( 24 ), and intra‐articular knee monosodium iodoacetate‐induced osteoarthritis ( 25 ).…”

“…Six days following STZ injection, blood glucose levels of the animals were measured using an Accu‐Chek Aviva® glucometer (Roche Diagnostics GmbH, Mannheim, Germany). Only rats with a blood glucose level of ≥15 mmol/L were considered diabetic and included in the study ( 31 , 32 , 33 , 34 , 35 ).…”

“…A bipolar, custom‐made DRGS lead was implanted as previously described ( 20 , 21 , 22 , 23 , 27 ). Briefly, a paravertebral incision was made, and the intravertebral foramen of L4 was exposed.…”

“…Animals were externally stimulated for 30 min with Con‐DRGS (20 Hz, 0.2 msec pulse width, amplitude at 67% of the motor threshold [MT]) or Sham‐DRGS (amplitude at 0% MT) using a Proclaim implantable pulse generator (Abbott, Inc., TX, USA) in the first week following DRGS implantation ( 31 , 32 ). The MT was measured before stimulation onset using a frequency of 2 Hz, and pulse width of 0.2 msec.…”

“…Dorsal root ganglion stimulation (DRGS) is a promising novel addition to the field of neuromodulation, with advantages over SCS in terms of a smaller charge requirement, better dermatomal coverage, and efficacy in the treatment of complex regional pain syndrome ( 15 , 16 , 17 , 18 ). Over the years, an increasing amount of literature has been published on the analgesic properties of DRGS, including both clinical ( 19 ) and rodent studies ( 20 , 21 , 22 , 23 , 24 , 25 ). Whereas SCS is thought to only recruit Aβ‐fibers, DRGS can theoretically stimulate not only Aβ‐, but also C‐ and Aδ‐fibers due to the unique properties of the DRG ( 26 ).…”