Antihyperalgesia by alpha 2-GABA(A) Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites

作者：Paul Jolly; Yevenes Gonzalo E; Benke Dietmar; Di Lio Alessandra; Ralvenius William T; Witschi Robert; Scheurer Louis; Cook James M; Rudolph Uwe; Fritschy Jean Marc; Zeilhofer Hanns Ulrich^*

来源：Neuropsychopharmacology, 2014, 39(2): 477-487.

DOI：10.1038/npp.2013.221

• neuropathic pain
• analgesia
• GABA
• benzodiazepine
• spinal cord
• mouse model

Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABA(A) receptors (GABA(A)Rs) containing alpha 2 subunits (alpha 2-GABA(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(A)Rs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABA(A)R-mutated mice, which either lack alpha 2-GABA(A)Rs specifically from the spinal cord, or, which express only benzodiazepine-insensitive alpha 2-GABA(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(A)Rs were benzodiazepine insensitive. The major (alpha 2-dependent) component of GABA(A)R-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal alpha 2-GABA(A)Rs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target alpha 2-GABA(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.

• 出版日期2014-1