henryaj

(with apologies to Sasha Shulgin) Gabapentinoids are weird. For a start, they don’t do what they say on the tin. It was named after the thing the inventors thought it would do, i.e. bind to and modulate GABA receptors, the ones which cause sedation and anxiolysis. But they have no activity at these receptors. Intuitively then they wouldn’t have an effect on sleep or anxiety. They also don’t bind to dopamine receptors — you would think then that they wouldn’t be helpful for psychosis (most antipsychotics antagonise dopamine receptors). And they don’t bind to opioid receptors, so they’re surely not useful for treating pain. But they do! Gabapentinoids are prescribed for sleep, anxiety, bipolar disorder, and epilepsy, as well as neuropathic pain and restless legs syndrome. Ok so what do they bind to then Gabapentinoids bind to the α2δ protein, a subunit of voltage-gated calcium channels (hence their alternative name of α2δ ligands). Usually the concentration of calcium ions outside the cell is thousands of times higher than inside; these channels respond to a voltage by opening and allowing calcium to flood in. Depending on the cell they’re attached to, this can cause muscle contraction, neuronal signalling, and protein synthesis. Specifically they bind α2δ-1 and α2δ-2, but only exert their effect through the former (as proven by trials on α2δ-2-knockout mice). There seems to be an as-yet undiscovered natural ligand for α2δ-1 and -2 which binds to the same site as gabapentinoids. Importantly they don’t block calcium channels — instead they inhibit the release of monoamines (serotonin, norepinephrine, dopamine) and substance P1 triggered by calcium influx. They also inhibit calcium channel-dependent release of glutamate and glycine in various brain tissues. Sensitized calcium channels There are states in which calcium channels become ‘sensitized’, such as in the case of neuronal injury, and gabapentinoids might selectively work in these conditions. * Activa