Release of γ-Aminobutyric Acid in the Dorsal Horn and Suppression of Tactile Allodynia by Spinal Cord Stimulation in Mononeuropathic Rats

Stiller, Carl‐Olav; Cui, Jiujie; O’Connor, W.T.; Brodin, Ernst; Meyerson, Björn A.; Linderoth, Bengt

doi:10.1097/00006123-199608000-00026

Cited by 290 publications

(205 citation statements)

References 39 publications

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“…28 It is of special interest that this effect on the GABA system occurred only in rats that in preceding experiments had been found to respond to SCS with significant suppression of hind paw hypersensitivity. 29 These results confirm earlier observations that the state of central hyperexcitability manifested in the development of allodynia after peripheral nerve injury relates to dysfunction of the spinal GABA systems, and it appears that SCS may act by restoring normal GABA levels in the dorsal horn. These findings were supplemented by behavioral experiments where we showed that that the allodynia-suppressive effect of SCS could be counteracted by intrathecal injection of a GABA B antagonist whereas the GABA A antagonist bicuculline was less effective.…”

Section: What Is Known About Transmitter Mechanisms Involved In Scs?supporting

confidence: 90%

Mode of Action of Spinal Cord Stimulation in Neuropathic Pain

Meyerson

Linderoth

2006

Journal of Pain and Symptom Management

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143

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Spinal cord stimulation emerged as a spin-off from the classical gate-control theory, which, however, does not suffice to explain its clinical effects. Whether or not nociceptive forms of pain may be attenuated remains a controversial issue. Previous experimental studies aiming at elucidating the underlying mechanisms were performed on intact, anesthetized animals and were therefore of limited clinical relevance.

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Section: What Is Known About Transmitter Mechanisms Involved In Scs?supporting

confidence: 90%

Mode of Action of Spinal Cord Stimulation in Neuropathic Pain

Meyerson

Linderoth

2006

Journal of Pain and Symptom Management

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143

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“…The current study also shows that blockade of GABA A receptors in the spinal cord prevents the antihyperalgesia produced by high frequency TENS. Similarly, prior studies show increased extracellular concentrations of GABA in the spinal cord during dorsal column stimulation, at high frequency, also begins after removal of the stimulation and utilizes GABA receptors in the spinal cord to produce analgesia (Linderoth et al, 1994;Stiller et al, 1996). Dorsal column stimulation, delivered at sensory intensity and high frequency, would activate large diameter afferent fibers similar to TENS delivered at sensory intensity and high frequency .…”

Section: Gaba and High Frequency Tensmentioning

confidence: 80%

“…Supraspinal activation of mu-opioid receptors increases release of GABA in the spinal cord that is prevented by 5-HT 3 receptor antagonists (Kawamata et al, 2002). Indeed, dorsal column stimulation at high frequency (100 Hz), which would activate large diameter sensory afferents like TENS, also increases spinal release of GABA in normal animals and those with nerve injury (Linderoth et al, 1994;Stiller et al, 1996), and reduces glutamate release through activation of GABA B receptors (Cui et al, 1997). These data suggest that analgesia mediated by supraspinal μ-opioid receptors releases serotonin in the spinal cord that in turn activates 5-HT 3 receptors on GABAergic neurons resulting in release of GABA.…”

Section: Introductionmentioning

confidence: 99%

Release of GABA and activation of GABAA in the spinal cord mediates the effects of TENS in rats

et al. 2007

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Transcutaneous electrical nerve stimulation (TENS) is a commonly utilized non-pharmacological, non-invasive treatment for pain. GABA is a neurotransmitter in the dorsal horn of the spinal cord that mediates analgesia locally, and also through activation of supraspinal sites. TENS reduces hyperalgesia through activation of receptor-mediated pathways at the level of the spinal cord, and supraspinally. The current study tested the hypothesis that either high or low frequency TENS applied to the inflamed knee joint increases GABA in the spinal cord dorsal horn and activates GABA receptors spinally. We utilized microdialysis to sample the extracellular fluid before, during and after TENS and analyzed GABA in dialysates with high performance liquid chromatography. We analyzed the extracellular GABA concentrations in animals with and without knee joint inflammation induced by intra-articular injection of kaolin and carrageenan. We further tested if spinal blockade of GABA receptors prevents the antihyperalgesia produced by TENS in rats with joint inflammation. We show that high frequency TENS increases extracellular GABA concentrations in the spinal cord in animals with and without joint inflammation. The increases in GABA do not occur in response to low frequency TENS, and there are no increases in glycine in response to low or high frequency TENS. However, the reduction in primary hyperalgesia by both high and low frequency TENS is prevented by spinal blockade of GABA A receptors with bicuculline. Thus, high frequency TENS increases release of GABA in the deep dorsal horn of the spinal cord, and both high and low frequency TENS reduce primary hyperalgesia by activation of GABA A receptors spinally.

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“…Activity-dependent central sensitization (heterosynaptic facilitation) is evident within seconds of a nociceptive conditioning stimulus and can outlast the stimulus for hours (Woolf and Wall, 1986). Within the dorsal horn, increases in excitatory amino acid concentrations (Somers et al, 2002) and reduction of GABA concentrations (Ibuki et al, 1997;Stiller et al, 1996) may also contribute to allodynia and hyperalgesia after nerve injury. The present results also suggest that upregulated expression of Na v 1.3 contributes to hyperresponsiveness of these central neurons after nerve injury.…”

Section: Discussionmentioning

confidence: 99%

Altered Sodium Channel Expression in Second-Order Spinal Sensory Neurons Contributes to Pain after Peripheral Nerve Injury

Hains

Saab²,

Klein³

et al. 2004

J. Neurosci.

249

156

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Peripheral nerve injury is known to upregulate the rapidly repriming Na v 1.3 sodium channel within first-order spinal sensory neurons. In this study, we hypothesized that (1) after peripheral nerve injury, second-order dorsal horn neurons abnormally express Na v 1.3, which (2) contributes to the responsiveness of these dorsal horn neurons and to pain-related behaviors. To test these hypotheses, adult rats underwent chronic constriction injury (CCI) of the sciatic nerve. Ten days after CCI, allodynia and hyperalgesia were evident. In situ hybridization, quantitative reverse transcription-PCR, and immunocytochemical analysis revealed upregulation of Na v 1.3 in dorsal horn nociceptive neurons but not in astrocytes or microglia, and unit recordings demonstrated hyperresponsiveness of dorsal horn sensory neurons. Intrathecal antisense oligodeoxynucleotides targeting Na v 1.3 decreased the expression of Na v 1.3 mRNA and protein, reduced the hyperresponsiveness of dorsal horn neurons, and attenuated pain-related behaviors after CCI, all of which returned after cessation of antisense delivery. These results demonstrate for the first time that sodium channel expression is altered within higher-order spinal sensory neurons after peripheral nerve injury and suggest a link between misexpression of the Na v 1.3 sodium channel and central mechanisms that contribute to neuropathic pain after peripheral nerve injury.

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Release of γ-Aminobutyric Acid in the Dorsal Horn and Suppression of Tactile Allodynia by Spinal Cord Stimulation in Mononeuropathic Rats

Cited by 290 publications

References 39 publications

Mode of Action of Spinal Cord Stimulation in Neuropathic Pain

Mode of Action of Spinal Cord Stimulation in Neuropathic Pain

Release of GABA and activation of GABAA in the spinal cord mediates the effects of TENS in rats

Altered Sodium Channel Expression in Second-Order Spinal Sensory Neurons Contributes to Pain after Peripheral Nerve Injury

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