Antihyperalgesia by alpha 2-GABA sub(A) Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites
Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABA sub(A) receptors (GABA sub(A)Rs) containing alpha 2 subunits ( alpha 2-GABA sub(A)Rs). Previous work indicates that potentiation of these rec...
Gespeichert in:
Veröffentlicht in: | Neuropsychopharmacology (New York, N.Y.) N.Y.), 2014-01, Vol.39 (2), p.477-487 |
---|---|
Hauptverfasser: | , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABA sub(A) receptors (GABA sub(A)Rs) containing alpha 2 subunits ( alpha 2-GABA sub(A)Rs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal alpha 2-GABA sub(A)Rs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABA sub(A)R-mutated mice, which either lack alpha 2-GABA sub(A)Rs specifically from the spinal cord, or, which express only benzodiazepine-insensitive alpha 2-GABA sub(A)Rs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all alpha 2-GABA sub(A)Rs were benzodiazepine insensitive. The major ( alpha 2-dependent) component of GABA sub(A)R-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal alpha 2-GABA sub(A)Rs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target alpha 2-GABA sub(A)Rs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions. |
---|---|
ISSN: | 0893-133X |
DOI: | 10.1038/npp.2013.221 |