title: Reversal of pathological pain through specific spinal GABAA receptor subtypes.
abstract: 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.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Knabl
authors.forename: Robert
authors.initials: R
authors.lastname: Witschi
authors.forename: Katharina
authors.initials: K
authors.lastname: Hösl
authors.forename: Heiko
authors.initials: H
authors.lastname: Reinold
authors.forename: Ulrike B
authors.initials: UB
authors.lastname: Zeilhofer
authors.forename: Seifollah
authors.initials: S
authors.lastname: Ahmadi
authors.forename: Johannes
authors.initials: J
authors.lastname: Brockhaus
authors.forename: Marina
authors.initials: M
authors.lastname: Sergejeva
authors.forename: Andreas
authors.initials: A
authors.lastname: Hess
authors.forename: Kay
authors.initials: K
authors.lastname: Brune
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
authors.forename: Hanns
authors.initials: H
authors.lastname: Möhler
authors.forename: Hanns Ulrich
authors.initials: HU
authors.lastname: Zeilhofer
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002211:Capsaicin / Q000494:pharmacology; D002908:Chronic Disease / Q000188:drug therapy; D003975:Diazepam / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D005464:Fluorobenzenes / Q000378:metabolism / Q000494:pharmacology; D005557:Formaldehyde; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006358:Hot Temperature; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000517:prevention & control; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000700:Analgesics; D005464:Fluorobenzenes; D020033:Protein Isoforms; D021122:Protein Subunits; D011963:Receptors, GABA-A; D014230:Triazoles; D005557:Formaldehyde; C409903:L 838,417; D003975:Diazepam; D002211:Capsaicin