This is a detailed technical article expanding on my previous post about new research on preventing hyperalgesia from opiates (with excellent explanatory diagrams online).
KCC2-selective compound restores impaired chloride transport in neurons and improves hypersensitivity in rat model of neuropathic pain.
The potassium-chloride cotransporter KCC2 might seem an unlikely target for the next generation of pain medications. The humble protein, found on neurons in the dorsal horn of the spinal cord and throughout the central nervous system, serves the mundane task of pumping chloride out of cells. But KCC2 has recently emerged as a key regulator of neuronal signaling.
A new report from Yves De Koninck and colleagues at Université Laval and Institut Universitaire en Santé Mentale de Québec, Canada, now debuts a compound that bolsters KCC2 activity and normalizes cell electrophysiology as well as pain hypersensitivity in a rat model of neuropathic pain
The problem arises when KCC2 activity falls following downregulation by brain-derived neurotrophic factor (BDNF), a key intercellular signaling molecule. The source of BDNF and the events leading up to loss of KCC2 activity vary; the deficit has been shown to underlie aspects of pain conditions including neuropathic and inflammatory pain as well as morphine-induced hypersensitivity
Without KCC2 activity, chloride accumulates inside cells, and the chloride gradient collapses. This changes the reversal potential of ion channels that pass chloride, such as the main receptor for the inhibitory neurotransmitter GABA
Chloride ions normally flow down their electrochemical gradient into cells to hyperpolarize the membrane potential and inhibit cell firing, but the collapse leads to a less efficacious inhibitory current. This loss of inhibitory signaling in the spinal cord is thought to contribute to the pain hypersensitivity that accompanies neuropathic pain.
the team zeroed in on a handful of compounds including CLP257.
In pathological conditions, loss of KCC2 activity causes accumulation of intracellular chloride in neurons, which impairs GABA receptor-mediated inhibition, causing hyperexcitability characteristic of neuropathic pain. By enhancing KCC2 activity, CLP257 reduces intracellular chloride and restores the ability of the nervous system to control its own activity such as endogenous pain control.
In normal cells, KCC2 activity keeps intracellular chloride very low
“There may be a light at the end of the tunnel in terms of developing non-sedative, non-opioid drugs for pain.”
On the other hand, he cautioned, this compound may not see the light of day as a medication—drug development can fail for many reasons. “But it gives hope that there are emerging ways of solving the problem.”