Decreased intracellular GABA levels contribute to spinal cord stimulation-induced analgesia in rats suffering from painful peripheral neuropathy: The role of KCC2 and GABAA receptor-mediated inhibition
Autor: | M. van Kleef, S. Gerard, Elbert A.J. Joosten, Marjolein Raijmakers, Sofie Janssen, Michiel Truin |
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Přispěvatelé: | Anesthesiologie, MUMC+: MA Anesthesiologie (9), RS: MHeNs School for Mental Health and Neuroscience |
Rok vydání: | 2012 |
Předmět: |
Male
medicine.medical_specialty KCC2 Electric Stimulation Therapy Neurotransmission Chronic neuropathic pain Synaptic Transmission gamma-Aminobutyric acid Rats Sprague-Dawley GABA Cellular and Molecular Neuroscience Internal medicine medicine Extracellular Animals Receptor gamma-Aminobutyric Acid Symporters integumentary system GABAA receptor Chemistry Peripheral Nervous System Diseases GABA(A) receptor Neural Inhibition Cell Biology Receptors GABA-A Spinal cord Rats Disease Models Animal Endocrinology medicine.anatomical_structure Spinal Cord Spinal cord stimulation nervous system Neuralgia GABAergic Sciatic nerve Analgesia Chronic Pain tissues Neuroscience medicine.drug |
Zdroj: | Neurochemistry International, 60(1), 21-30. Elsevier Limited |
ISSN: | 0197-0186 |
Popis: | Elevated spinal extracellular gamma-aminobutyric acid (GABA) levels have been described during spinal cord stimulation (SCS)-induced analgesia in experimental chronic peripheral neuropathy. Interestingly, these increased GABA levels strongly exceeded the time frame of SCS-induced analgesia. In line with the former, pharmacologically-enhanced extracellular GABA levels by GABA(B) receptor agonists in combination with SCS in non-responders to SCS solely could convert these non-responders into responders. However, similar treatment with GABA(A) receptor agonists and SCS is known to be less efficient. Since K+ Cl- cotransporter 2 (KCC2) functionality strongly determines proper GABA(A) receptor-mediated inhibition, both decreased numbers of GABA(A) receptors as well as reduced KCC2 protein expression might play a pivotal role in this loss of GABA(A) receptor-mediated inhibition in non-responders. Here, we explored the mechanisms underlying both changes in extracellular GABA levels and impaired GABA(A) receptor-mediated inhibition after 30 min of SCS in rats suffering from partial sciatic nerve ligation (PSNL). Immediately after cessation of SCS, a decreased spinal intracellular dorsal horn GABA-immunoreactivity was observed in responders when compared to non-responders or sham SCS rats. One hour later however, GABA-immunoreactivity was already increased to similar levels as those observed in non-responder or sham SCS rats. These changes did not coincide with alterations in the number of GABA-immunoreactive cells. C-Fos/GABA double-fluorescence clearly confirmed a SCS-induced activation of GABA-immunoreactive cells in responders immediately after SCS. Differences in spinal dorsal horn GABA(A) receptor-immunoreactivity and KCC2 protein levels were absent between all SCS groups. However, KCC2 protein levels were significantly decreased compared to sham PSNL animals. In conclusion, reduced intracellular GABA levels are only present during the time frame of SCS in responders and strongly point to a SCS-mediated on/off GABAergic release mechanism. Furthermore, a KCC2-dependent impaired GABA(A) receptor-mediated inhibition seems to be present both in responders and non-responders to SCS due to similar KCC2 and GABA(A) receptor levels. |
Databáze: | OpenAIRE |
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