In the nineties we knew that baclofen was the
In the nineties we knew that (-)baclofen was the stereo-selective ligand for the GABAB receptor which had been recognised by Norman Bowery as a receptor for GABA, which was different from the GABAA receptor (Hill and Bowery, 1981). GABAB receptor antagonists were also synthesised and made available by the CIBA-Geigy laboratories (Olpe et al., 1990). However, it took a number of years for the gene encoding the metabotropic GABAB receptor to be cloned by Klemens Kaupmann and for GABAB1 and GABAB2 heterodimers to be identified as critical units for functional wnt signaling (Kaupmann et al., 1997, White et al., 1998). GABAB knock out mice were generated by the Novartis team 5 years after receptor cloning with the aim to establish the role of GABAB receptor in in vivo models of epilepsy, memory and pain (Schuler et al., 2001).
In the early 90's it became evident that the systemic administration of (±)baclofen resulted in analgesic and anti-hyperalgesic effects in experimental models of acute and chronic pain at doses which were significantly lower than those required for muscle-relaxation. Baclofen exerted antinociceptive effects when administered directly in the CNS by intrathecal and intracerebroventricular injections (Sawynok and LaBella, 1982, Wilson and Yaksh, 1978). Consistent with a central site of action for baclofen, GABAB receptor antagonists injected intrathecally were able to prevent the analgesic effect of systemic baclofen (Malcangio et al., 1991). Indeed, autoradiography binding studies demonstrated that GABAB receptors in the spinal cord were localized mainly in the superficial laminae of the dorsal horns where they were found on both primary afferent fibre terminals and intrinsic neurons (Malcangio et al., 1993, Price et al., 1984, Price et al., 1987). The expression of GABAB receptors in the dorsal horn showed plasticity and underwent up- or down-regulation after systemic treatment with receptor antagonists or baclofen (Malcangio et al., 1993). GABAB receptor plasticity explained the tolerance to the analgesic effect of baclofen that developed after prolonged treatments and it limited the chronic use of the drug (Malcangio et al., 1993). At the same time it was clear that baclofen-induced analgesia was effected through a novel pathway, independent from the opioid system as it was not reversed by naloxone. Equally, the pathway was distinct from GABAA receptor activation as the effect of baclofen was not blocked by bicuculline.
The cloning of the two GABAB receptor subunits demonstrated that GABAB receptors are metabotropic members of the seven transmembrane G-Protein coupled receptors superfamily, which belong to the same class as metabotropic glutamate receptors (mGluRs), calcium-sensing receptors and receptors for umani and sweet taste. GABAB receptor activation is associated with opening of inwardly rectifying potassium channels, inhibition of calcium channels and activation of adenylyl cyclase. GABAB receptors have a heterodimeric structure and complete receptor function requires the assembly of GABAB1 and GABAB2 subunits, which are linked by protein/protein interactions between their intracellular C-terminal domains. The GABA binding site is located on the extracellular domain of the GABAB1 subunit, whilst the GABAB2 subunit interacts with the G proteins and is essential for functional expression of the receptor. GABAB receptor subunits are found both centrally and peripherally including the thalamus, brain stem nuclei and spinal cord.
Acute and chronic pain Pain is a subjective experience associated with actual or potential tissue damage. It is a sensation in a part of our body that is also unpleasant, and therefore an emotional experience. Pain can be acute or chronic: acute pain is a warning system essential for survival and well-being whilst chronic pain does not serve any useful protective mechanism for the organism, outlasts the noxious stimulus and is poorly controlled by current analgesics (Woolf, 2010). The pain experience is mediated by specialised primary afferent fibres, namely the nociceptors, which detect noxious stimuli in the periphery and transmit electrical impulses centrally to the spinal cord on their way to the brain where pain is perceived. Interestingly, the underlying organization and strengthening of nociceptive circuitry in the dorsal horn in adulthood can be altered by sensory inputs in early life (Fitzgerald, 2005) and during early development GABA can induce depolarization due to reduced neuronal ability to extrude chloride ions (Baccei, 2016).