Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment(1,2). A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology(3-7). Facilitation of spinal gamma-aminobutyric acid ( GABA) ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss(8,9). With the use of GABA(A)-receptor point- mutated knock- in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine- site ligands(10-12), we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha 2 and/ or alpha 3 subunits. We show that their selective activation by the non- sedative ('alpha 1- sparing') benzodiazepine- site ligand L- 838,417 ( ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L- 838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative- emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype- selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.
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