Burst and Tonic Spinal Cord Stimulation Both Activate Spinal GABAergic Mechanisms to Attenuate Pain in a Rat Model of Chronic Neuropathic Pain

Koen P V Meuwissen; Luuk E de Vries; Jianwen Wendy Gu; Tianhe C Zhang; Elbert A J Joosten

doi:10.1111/papr.12831

Burst and Tonic Spinal Cord Stimulation Both Activate Spinal GABAergic Mechanisms to Attenuate Pain in a Rat Model of Chronic Neuropathic Pain

Pain Pract. 2020 Jan;20(1):75-87. doi: 10.1111/papr.12831. Epub 2019 Sep 9.

Authors

Koen P V Meuwissen^{1

2}, Luuk E de Vries², Jianwen Wendy Gu³, Tianhe C Zhang³, Elbert A J Joosten^{1

2}

Affiliations

¹ Department of Anesthesiology and Pain Management, Pain Management and Research Centre, MUMC+, Maastricht, The Netherlands.
² School for Mental Health and Neuroscience (MHeNS), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
³ Boston Scientific: Neuromodulation, Research and Advanced Concepts Team, Valencia, California, U.S.A.

Abstract

Background: Experimental and clinical studies have shown that tonic spinal cord stimulation (SCS) releases gamma-aminobutyric acid (GABA) in the spinal dorsal horn. Recently, it was suggested that burst SCS does not act via spinal GABAergic mechanisms. Therefore, we studied spinal GABA release during burst and tonic SCS, both anatomically and pharmacologically, in a well-established chronic neuropathic pain model.

Methods: Animals underwent partial sciatic nerve ligation (PSNL). Quantitative immunohistochemical (IHC) analysis of intracellular GABA levels in the lumbar L4 to L6 dorsal spinal cord was performed after 60 minutes of burst, tonic, or sham SCS in rats that had undergone PSNL (n = 16). In a second pharmacological experiment, the effects of intrathecal administration of the GABA_A antagonist bicuculline (5 μg) and the GABA_B antagonist phaclofen (5 μg) were assessed. Paw withdrawal thresholds to von Frey filaments of rats that had undergone PSNL (n = 20) were tested during 60 minutes of burst and tonic SCS 30 minutes after intrathecal administration of the drugs.

Results: Quantitative IHC analysis of GABA immunoreactivity in spinal dorsal horn sections of animals that had received burst SCS (n = 5) showed significantly lower intracellular GABA levels when compared to sham SCS sections (n = 4; P = 0.0201) and tonic SCS sections (n = 7; P = 0.0077). Intrathecal application of the GABA_A antagonist bicuculline (5 μg; n = 10) or the GABA_B antagonist phaclofen (5 μg; n = 10) resulted in ablation of the analgesic effect for both burst SCS and tonic SCS.

Conclusions: In conclusion, our anatomical and pharmacological data demonstrate that, in this well-established chronic neuropathic animal model, the analgesic effects of both burst SCS and tonic SCS are mediated via spinal GABAergic mechanisms.

Keywords: GABAA/B receptor antagonist; burst spinal cord stimulation; gamma-aminobutyric acid; mechanical hypersensitivity; peripheral nerve injury.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Ligation
Male
Neuralgia / metabolism*
Rats
Rats, Sprague-Dawley
Sciatic Nerve / injuries
Sciatic Nerve / surgery
Spinal Cord Stimulation / methods*
gamma-Aminobutyric Acid / metabolism*

Substances

gamma-Aminobutyric Acid