Chloride dysregulation: the next target for chronic pain therapeutics

Chronic pain affects a substantial fraction of the population, yet pharmacological management remains deeply inadequate. This failure likely reflects the focus on developing analgesics suppressing normal nociceptive signalling rather than correcting the pathological substrates distinguishing chronic from acute pain. Here we review how the identification of injury-induced downregulation of the potassium-chloride cotransporter KCC2 in spinal dorsal horn neurons represents a landmark. It first provided a mechanistic, long-term substrate for spinal inhibitory failure. This form of disinhibition had the potential to explain several cardinal symptoms of neuropathic pain; not just hyperalgesia, through spinal hyperexcitability, and tactile allodynia, through cross-talk between sensory modalities, but also spontaneous pain, through enabling spontaneous bursts of activity in spinal nociceptive output to emerge. A second landmark is that chloride dysregulation as a substrate of disinhibition yields non-linear, non-intuitive predictions of neural circuit behaviours that shed light on several features of chronic pain and its therapeutic challenges. One is paradoxical pro-excitatory actions of tapping into normally endogenous inhibitory neurotransmission, potentially explaining failures of benzodiazepines analgesia and of conditional pain modulation. Others include degradation of sensory processing, possibly explaining diffuse pain, and leaky plasticity, predisposing to catastrophic sensitization. In turn, mechanisms regulating KCC2 itself emerge as substrates of chronification, as well as substrates of opioid-induced maladaptive paradoxical hyperalgesia. Finally, divergent yet convergent signaling cascades underlying KCC2-downregulation reveal a form of pathway degeneracy across sexes with lessons for therapeutics. All-in-all, these findings position KCC2 as a key novel target, not just for analgesia, but also for disease modification.