The importance of being specific

Abstract

In this issue, you will find a paper by Vasović et al., entitled “Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6GABAA receptors” (Vasović et al., 2019). Loss of GABA-mediated inhibition within pain circuits is one of the mechanisms commonly invoked to explain allodynia and hyperalgesia following injury. Intrathecal administration of picrotoxin produces pain like signs. Positive allosteric modulators of GABAA receptors like benzodiazepines are known to produce analgesia although their main effects are sedative, hypnotic and anxiolytic, and therefore, their use as analgesics is curtailed (Schliessbach et al., 2017). GABAA receptors mediate fast neuronal inhibition, and they are widely expressed in the CNS modulating all sorts of functions. However, their structure is heterogeneous. They are formed by the ensemble of typically 5 protein subunits out of 19 possible with certain rules for combination. Structural heterogeneity opens up the door to designing new specific compounds targeting single receptor subunits thus binding to a subset of GABAA receptors and modulating a reduced range of functions or ideally a single function, like pain signalling. The strategy of developing specific pharmacological tools to interact with single GABA receptor subunits has been explored before (Munro, Hansen, & Mirza, 2013). Alpha5 preferring compounds have been shown to have potential for analgesia using animal models of inflammatory and neuropathic pain while having relatively low impact on other functions. However, the alpha 6 subunit does not contain a benzodiazepine site and it is insensitive to this class of compounds. The PAM activity of pyrazoloquinolinones at diazepam insensitive GABAA receptors has been studied since the 90s, and recently, it has been shown that certain drugs of this class can interact specifically with alpha6-containing receptors to potentiate chloride flow upon receptor activation (Treven et al., 2018). The commented article uses two pyrazoloquinolinones, one of which is active at modulating alpha6-containing GABA receptors (DK-I-56-1) and the other is inactive and serves as a control. The authors present electrophysiological proof for the PAM activity of DK-I-56-1 on receptors containing the alpha6 subunit. They also perform pharmacokinetic studies to show that this compound crosses the blood–brain barrier and has a good enough metabolic stability to ensure pharmacologically relevant levels of the compound during daily IP injections of the compound. Finally, they show that subchronic treatment with this compound produces clear signs of analgesia in rats that have undergone a lesion to the infraorbital nerve (a model of trigeminal neuropathic pain). Interestingly, these analgesic effects occur in the absence of ethologic signs of sedation and are not produced by the inactive compound. As a proof of mechanism, the results of this paper are very promising. This is a great job done! Unfortunately, this is only the beginning of a long and complicated road to success. GABA receptors containing alpha6 subunits are not exclusive of trigeminal ganglia. They are present in cerebellar granule cells and spinal motor neurons were they may mediate sensorimotor processing, in hippocampal interneurons perhaps modulating certain forms of depression and in other nuclei of the CNS mediating a variety of functions. Therefore, the potential use of this chemical family of compounds to produce analgesics for specific pain conditions, such as trigeminal neuropathy, is just starting to be analysed. On rational grounds, the strategy of developing new psychoactive compounds with highly specific profiles is definitively good, probably the best. The questions open to the future are how specific can we get and how specific is the linkage between receptor structure and body function. *In this issue, you will find a paper by Vasović et al.: ‘Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6GABAA receptors’. Eur J Pain, 23, 973-984