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.

Antihyperalgesic Effect of the GABAA Ligand Clobazam in a Neuropathic Pain Model in Mice: A Pharmacokinetic–Pharmacodynamic Study

“…PK parameters in the brain after oral administration of 3 and 10 mg/kg of clobazam (n = 6). The magnitude of this effect was comparable to the effect of diazepam [17]) and of the a2/a3 -subtype-selective BZD-site ligand HZ166 [18]. Similar to what is described in the literature for diazepam [3] and a2-a3 selective compounds [9,17,18], clobazam did not modify the response of the noninjured paw, suggesting that a facilitation of GABA A receptormediated inhibition at the spinal cord level is involved in the observed antihyperalgesia.…”

“…Such compounds were successfully tested in rats (L-838,417, for example [17]). They were, however, not further developed in human beings for pharmacokinetic reasons such as a poor bioavailability and short half-lives.…”

Acetazolamide attenuates chemical-stimulated but not thermal-stimulated acute pain in mice

“…Given that a reduction in locomotor activities after drug treatment may lead to a falsepositive result in evaluating the analgesic effect, we selected the proper doses of diazepam, AZA and MZA that did not affect locomotor activities. In fact, a previous study reported that diazepam achieved analgesia in inflammatory and neuropathic pain models at a dose not producing sedation [20] . Thus, we thought that the lower dose that we utilized might not be the main cause of the lack of an analgesic effect for diazepam.…”

Blockade of TNF-α rapidly inhibits pain responses in the central nervous system

“…Functional analysis was performed for mice and humans using Brain Voyager QX (Version 10.3) and our own software MagnAn (25), as previously described (28). In summary, after preprocessing [motioncorrected using sinc interpolation Gaussian spatial (human: FWHM = 4 mm, mouse: 0.469 mm) and temporal (FWHM = 3 volumes) smoothing], general linear modeling analysis with separate predictors for each stimulus was performed.…”