Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-4687
Knabl, J; Witschi, R; Hösl, K; Reinold, H; Zeilhofer, U B; Ahmadi, S; Brockhaus, J; Sergejeva, M; Hess, A; Brune, K; Fritschy, J M; Rudolph, U; Möhler, H; Zeilhofer, H U (2008). Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature, 451(7176):330-334.
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Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. 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, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-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.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Pharmacology and Toxicology|
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Date:||17 January 2008|
|Deposited On:||18 Nov 2008 16:29|
|Last Modified:||08 Mar 2014 19:08|
|Publisher:||Nature Publishing Group|
|Citations:||Web of Science®. Times Cited: 157|
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