Effectiveness of dorsal root ganglion stimulation and dorsal column spinal cord stimulation in a model of experimental painful diabetic polyneuropathy (original) (raw)
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CNS Neuroscience & Therapeutics, 2019
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 ipsilater...
Neuromodulation : journal of the International Neuromodulation Society, 2018
This study utilizes a model of long-term spinal cord stimulation (SCS) in experimental painful diabetic polyneuropathy (PDPN) to investigate the behavioral response during and after four weeks of SCS (12 hours/day). Second, we investigated the effect of long-term SCS on peripheral cutaneous blood perfusion in experimental PDPN. Mechanical sensitivity was assessed in streptozotocin induced diabetic rats (n = 50) with von Frey analysis. Hypersensitive rats (n = 24) were implanted with an internal SCS battery, coupled to an SCS electrode covering spinal levels L2-L5. The effects of four weeks of daily conventional SCS for 12 hours (n = 12) or Sham SCS (n = 12) were evaluated with von Frey assessment, and laser Doppler imaging (LDI). Average paw withdrawal thresholds (PWT) increased during long-term SCS in the SCS group, in contrast to a decrease in the Sham group (Sham vs. SCS; p = 0.029). Twenty-four hours after long-term SCS average PWT remained higher in the SCS group. Furthermore, ...
Neuromodulation : journal of the International Neuromodulation Society, 2018
The dorsal root ganglion (DRG) has been identified as an important neural structure in the development and maintenance of chronic pain. We present a retrospective case series of patients with refractory painful diabetic peripheral neuropathy (PDPN) that underwent electrical stimulation of the DRG and report on changes in their overall perceived pain and complication rates. Ten diabetic males (mean age 65.2 [SD 8.8] years) with painful symptoms of the lower limbs were enrolled and trialed with up to four quadripolar percutaneous DRG stimulation leads between L2 and L5 spinal levels. Patients received a fully implantable neurostimulation system (Abbott Laboratories, Sunnyvale, CA, USA) immediately or after a successful trial period (>50% reduction in pain). Overall perceived pain was measured by visual analogue scale (VAS) at baseline, one-week postimplantation and one-, three-, six-, and twelve-month follow-up (n = 5). Ten patients were included in this retrospective study. Seven ...
Contemporary Insights into Painful Diabetic Neuropathy and Treatment with Spinal Cord Stimulation
Current Pain and Headache Reports, 2011
A substantial body of literature is available on the natural history of diabetes, but much less is understood of the natural history of painful diabetic peripheral neuropathy (PDPN), a pervasive and costly complication of diabetes mellitus. Multiple mechanisms have been proposed, including polyol pathway activation, advanced glycosylation end-product formation, and vasculopathic changes. Nevertheless, specific treatment modalities addressing these basic issues are still lacking. The mainstay of treatment includes pharmacological management with antidepressants, anticonvulsants, and opioids, but these drugs are often limited by unfavorable side-effect profiles. For over 30 years, spinal cord stimulation (SCS) has been used extensively for the management of various chronic neuropathic pain states. In the past decade, interest in the use of SCS for treatment of PDPN has increased. This article reviews pathophysiological mechanisms of PDPN, proposed mechanisms of SCS, and the role of SCS for the treatment of PDPN.
Journal of Pain Research
Low-intensity 10 kHz spinal cord stimulation (SCS) has been shown to provide pain relief in patients with chronic pain resulting from diabetic peripheral neuropathy (DPN). However to date, there have been no studies of 10 kHz SCS in animal models of diabetes. We aimed to establish correlative data of the effects of this therapy on behavioral and electrophysiological measures in a DPN model. Methods: Twenty-five adult male Sprague-Dawley rats were injected once intraperitoneally with 60 mg/kg streptozotocin (STZ) to induce diabetes over a subsequent 4 w period, while 4 naïve control animals were not injected. After approximately 21 d, 12 of STZinjected rats had mini epidural SCS leads implanted: 8 received continuous low intensity (~30% motor threshold) 10 kHz SCS, and 4 received sham SCS (0 mA) over 7 d. Behavioral assays (von Frey filament probe of hindpaw) were measured in 18 animals and in vivo dorsal horn electrophysiological studies (receptive field; response to afferent brush, von Frey probe, pinch) were performed in 17 animals. Results: Across behavioral assays of mechanical allodynia and electrophysiological assays of receptive field size and mechanosensitivity, diabetic animals stimulated with 10 kHz SCS showed statistically significant improvements compared to sham SCS. Conclusion: Low-intensity 10 kHz SCS produced several measures associated with a reduction of pain in diabetic rodent models that may help explain the clinical benefits of 10 kHz SCS in patients with painful diabetic neuropathy.
Frontiers in Neuroscience, 2020
Diabetic peripheral neuropathic pain (DPNP) is the most devastating complication of diabetes mellitus. Unfortunately, successful therapy for DPNP remains a challenge because its pathogenesis is still elusive. However, DPNP is believed to be due partly to abnormal hyperexcitability of dorsal root ganglion (DRG) neurons, but the relative contributions of specific functional subtypes remain largely unknown. Here, using the strepotozotocin (STZ) rat model of DPNP induced by a STZ injection (60 mg/kg, i.p), and intracellular recordings of action potentials (APs) from DRG neurons in anesthetized rats, we examined electrophysiological changes in C-and Aβ-nociceptive and Aβ-low threshold mechanoreceptive (LTM) neurons that may contribute to DPNP. Compared with control, we found in STZ-rats with established pain hypersensitivity (5 weeks post-STZ) several significant changes including: (a) A 23% increase in the incidence of spontaneous activity (SA) in Aβ-LTMs (but not C-mechanosensitive nociceptors) that may cause dysesthesias/paresthesia suffered by DPNP patients, (b) membrane hyperpolarization and a ∼85% reduction in SA rate in Aβ-LTMs by K v 7 channel activation with retigabine (6 mg/kg, i.v.) suggesting that K v 7/M channels may be involved in mechanisms of SA generation in Aβ-LTMs, (c) decreases in AP duration and in duration and amplitude of afterhyperpolarization (AHP) in C-and/or Aβ-nociceptors. These faster AP and AHP kinetics may lead to repetitive firing and an increase in afferent input to the CNS and thereby contribute to DPNP development, and (d) a decrease in the electrical thresholds of Aβ-nociceptors that may contribute to their sensitization, and thus to the resulting hypersensitivity associated with DPNP.
Diabetes care, 2014
Painful diabetic peripheral neuropathy (PDPN) is a common complication of diabetes mellitus. Unfortunately, pharmacological treatment is often partially effective or accompanied by unacceptable side effects, and new treatments are urgently needed. Small observational studies suggested that spinal cord stimulation (SCS) may have positive effects. We performed a multicenter randomized clinical trial in 36 PDPN patients with severe lower limb pain not responding to conventional therapy. Twenty-two patients were randomly assigned to SCS in combination with the best medical treatment (BMT) (SCS group) and 14 to BMT only (BMT group). The SCS system was implanted only if trial stimulation was successful. Treatment success was defined as ≥50% pain relief during daytime or nighttime or "(very) much improved" for pain and sleep on the patient global impression of change (PGIC) scale at 6 months. Trial stimulation was successful in 77% of the SCS patients. Treatment success was obser...
Diabetes Care, 2015
Spinal cord stimulation (SCS) has been demonstrated to serve as a successful second-line treatment modality for painful diabetic peripheral neuropathy (PDPN), as documented in two randomized clinical trials (RCTs) (1,2). Besides the fact that these two RCTs demonstrate a pain-relieving effect for a period of 6 months after the start of SCS treatment, only small observational studies suggest a long-term sustained effect in PDPN (3-5). In this article, we present the 24-month followup data of our recently published RCT in Diabetes Care (1). Thirty-six patients were enrolled in this study, and after randomization, 22 patients with PDPN in the lower limbs (15 male, mean age 57.1 years [SD 12.4], years of PDPN 6.0 [SD 5.1]) were assigned to the SCS group. A 2-week trial stimulation was performed to evaluate sufficient pain relief. After 6 months, 93% of patients in the control group crossed over to receive SCS. Treatment success of SCS was predefined in the protocol as $50% relief of pain intensity on a numeric rating scale (NRS) for 4 days during the daytime or nighttime or "(very) much improved" for pain and sleep on the patient global impression of change (PGIC) scale at 24 months. Additional outcome parameters were Figure 1-Mean pain scores at daytime and nighttime.
Treatment of painful diabetic neuropathy
Therapeutic Advances in Chronic Disease, 2014
NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions.