Abstract
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 2 subunits (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 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 2-GABA A Rs specifically from the spinal cord, or, which express only benzodiazepine-insensitive 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 2-GABA A Rs were benzodiazepine insensitive. The major (2-dependent) component of GABA A R-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal 2-GABA A Rs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target 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.
Original language | English (US) |
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Pages (from-to) | 477-487 |
Number of pages | 11 |
Journal | Neuropsychopharmacology |
Volume | 39 |
Issue number | 2 |
DOIs | |
State | Published - Jan 2014 |
Externally published | Yes |
Keywords
- GABA
- analgesia
- benzodiazepine
- mouse model
- neuropathic pain
- spinal cord
ASJC Scopus subject areas
- Pharmacology
- Psychiatry and Mental health