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GABAB receptors are proteins that can be found on the surface of nerve cells (i.e. neurones), and upon which GABA (a substance that mediates the transfer of electrical signals between neurons) interacts to produce a number of physiological effects. Our result can be broken down in the following points:
i) We have produced a detailed map of the distribution of GABAB receptors in spinal cord, as well as in the thalamus and cortex.
ii) We have provided the first description of the electrical events that occur in thalamic and cortical neurons during an absence epilepsy seizure, and found that in a naturally occurring animal model of this disease there is an increased expression of GABAB receptors prior to the onset of seizures.
iii) We have characterized some of the abnormal genes that are present in a naturally occurring animal model of absence epilepsy.
iv) We have obtained a detailed map of the brain structures that are activated during the development of chronic pain, and demonstrated that two different GABAB receptors in the spinal cord are involved in the modulation of pain and muscle relaxation, respectively.
In summary, this result has provided a number of important discoveries that are already guiding a more targeted approach to the development of new anti-absence and anti-pain medicines acting on GABAB receptors and the analysis of genetic abnormalities in absence epilepsy sufferers.
Our work has been the first to show that the distribution of GABABR1 and GABABR2 do not fully overlap (indicating that yet undiscovered GABABR subunits must be present in the brain) and that GABABR1a and GABABR2 can form functional GABABRs that are capable of modulating Ca2+ currents. Our results also showed that in the spinal cord GABABR1 is likely to have a preferential pre-synaptic location, and that in DRG cells all the modulation of high voltage activated Ca2+ currents is mediated by GABABR1.
As far as absence epilepsy is concerned, our work in the genetic GAERS model has provided the first description of the intracellular activity of cortical and thalamic neurones during spontaneous SWDs. In particular, they have highlighted the absence of rhythmic GABAB IPSPS in thalamocortical (TC) neurons and the presence of high frequency potentials in NRT cells, that are likely to be mediated by electrical coupling. Although the tonic hyperpolarization that is present in TC and cortical neurons might represent a very long lasting GABABR-mediated IPSPs, an action at the pre-synaptic level should also be strongly considered as the mechanism for the block of absence seizures by GABABR antagonists (see below).
Our work also demonstrated that in GAERS there is a stronger GABABR1 and GABABR2 immunostaining in selected thalamic/cortical regions/cells, together with an increased GABA level in the thalamus. In addition, the ability of baclofen to modulate thalamic GABA release is also enhanced in GAERS, suggesting that the increased immunostaining might be related to pre-synaptic receptors. Interestingly, these changes might be linked to the genetic abnormality leading to spike and wave discharges (SWDs) as most of them are observed well before the development of absence seizures.
By demonstrating that ethosuximide reduces both the persistent sodium current and the calcium-activated potassium current in TC and cortical neurons, we have provided conclusive evidence to resolve the unfortunately long lasting controversy concerning the action of the anti-absence drug ethosuximide. Moreover, we have shown that GABABR antagonists act by inhibiting the mechanisms responsible for the generation of SWDs, in contrast to ethosuximide that preferentially decreases the duration of SWDs but is unable to block their generation.
As far as pain is concerned, we have shown that although GABABRs inhibit the nociceptive input at spinal level, they also influence nociceptive transmission at supraspinal sites, sometimes with opposite effects. The spinal motor system seems to be rather more sensitive to the activation of GABABRs than the sensory system. Thus, the systemic injection of GABABR agonists, at the high doses necessary to cause hypoalgesia, is also very likely to evoke motor effects. This may explain the limited clinical use of systemic baclofen as an analgesic, despite the large experimental evidence pointing to that effect. The existence of multiple subunits/isoforms may allow searching for �effect-specific� ligands that could discriminate between the analgesic and antispatic effects of GABABR activation.
Our work has also been the first to show that the neuronal activity during chronic painful mono-arthritis is increased in many spinal and supra-spinal structures, but with a biphasic temporal pattern that is not correlated with the behavioral findings. This most likely results from the presence of multiple and complex facilitators and inhibitory transmitter systems involved in the central processing of chronic pain. An adaptive increase of inhibitory mechanisms seems to occur, and further research may provide important improvements in the treatment of chronic pain.
Another major finding of our work has been the discoveries that GABABR antagonists increase the expression of brain neurotrophins. As these substances promote recovery of nervous tissue after brain insults and as we have also shown that the binding of GABABR antagonists in AD patients is not affected, this finding suggests a novel avenue for the treatment of neurodegenerative diseases.
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