Reversal of pathological pain through specific spinal GABAA receptor subtypes.
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.
Knabl
Julia
J
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
Witschi
Robert
R
Hösl
Katharina
K
Reinold
Heiko
H
Zeilhofer
Ulrike B
UB
Ahmadi
Seifollah
S
Brockhaus
Johannes
J
Sergejeva
Marina
M
Hess
Andreas
A
Brune
Kay
K
Fritschy
Jean-Marc
JM
Rudolph
Uwe
U
Möhler
Hanns
H
Zeilhofer
Hanns Ulrich
HU
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
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