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

Abstract

BackgroundExperimental 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.MethodsAnimals 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 GABAA antagonist bicuculline (5 μg) and the GABAB 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.ResultsQuantitative 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 GABAA antagonist bicuculline (5 μg; n = 10) or the GABAB antagonist phaclofen (5 μg; n = 10) resulted in ablation of the analgesic effect for both burst SCS and tonic SCS.ConclusionsIn 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.

Modulation of mechanosensory vibrissal responses in the trigeminocervical complex by stimulation of the greater occipital nerve in a rat model of trigeminal neuropathic pain

“…The separate or combined blockade of GABA or Glycine transmission revealed a complex involvement of inhibitory circuits in the effects of GON stimulation on vibrissal responses, and strongly suggests that the synaptic weight of GABAergic and Glycinergic inputs modulating GON and vibrissal inputs is not the same, under either control or CCI-IoN conditions. This complexity was compounded by the uncontrolled degree of penetration of the drugs, a variable in the design intended to mimic the effects of applying agonists or antagonists of inhibitory neurotransmitters intrathecally or intracisternally in basic research [106][107][108][109][110] and clinical settings [111,112]. Yet, our findings may be supported by known local connections in the dorsal horn and provide new data on the possible involvement of these circuits under conditions of neuropathic pain.…”

Modulation of mechanosensory vibrissal responses in the trigeminocervical complex by stimulation of the greater occipital nerve in a rat model of trigeminal neuropathic pain

“…The separate or combined blockade of GABA or Glycine transmission revealed a complex involvement of inhibitory circuits in the effects of GON stimulation on vibrissal responses, and strongly suggests that the synaptic weight of GABAergic and Glycinergic inputs modulating GON and vibrissal inputs is not the same, under either control or CCI-IoN conditions. This complexity was compounded by the uncontrolled degree of penetration of the drugs, a variable in the design intended to mimic the effects of applying agonists or antagonists of inhibitory neurotransmitters intrathecally or intracisternally in both basic research [ 109 – 113 ] and clinical settings [ 114 , 115 ]. Yet, our findings may be supported by known local connections in the dorsal horn and provide new data on the possible involvement of these circuits under conditions of neuropathic pain.…”

Modulation of mechanosensory vibrissal responses in the trigeminocervical complex by stimulation of the greater occipital nerve in a rat model of trigeminal neuropathic pain

“…The separate or combined blockade of GABA or Glycine transmission revealed a complex involvement of inhibitory circuits in the effects of GON stimulation on vibrissal responses, and strongly suggests that the synaptic weight of GABAergic and Glycinergic inputs modulating GON and vibrissal inputs is not the same, under either control or CCI-IoN conditions. This complexity was compounded by the uncontrolled degree of penetration of the drugs, a variable in the design intended to mimic the effects of applying agonists or antagonists of inhibitory neurotransmitters intrathecally or intracisternally in both basic research [109][110][111][112][113] and clinical settings [114,115]. Yet, our ndings may be supported by known local connections in the dorsal horn and provide new data on the possible involvement of these circuits under conditions of neuropathic pain.…”