Augmentation of Spinal Inhibitory Neurotransmission via Restoration of Chloride Homeostasis and Modulation of Glycinergic Neurotransmission as Potential Pathways to Treat Chronic Pain

The prevalence of chronic pain in the general population ranges from 13 to 25%. Yet, despite the high level of prevalence and enormous socioeconomic burden incurred, pharmacological treatment of chronic pain remains limited as it is often refractory to currently available analgesics and many of these agents induce severe dose-limiting side effects or present a risk of tolerance, addiction, and abuse. The dearth of effective therapeutics for chronic pain has led to an over-reliance on opioid medications, which have helped fuel the current opioid epidemics faced worldwide. Thus, the discovery and development of more effective analgesics that avoid the opioid pathway and are devoid of abuse and addiction liabilities remains a critical unmet need. Among the myriad of maladaptive processes contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Specifically, disruption of glycinergic neurotransmission, together with changes in the anion gradient, play pivotal roles in the amplification of spinal pain signaling. Thus, it has been hypothesized that agents capable of restoring physiological neuronal chloride gradients or augmenting glycinergic tone within the dorsal horn may be able to obtund aberrant nociceptor signaling to the brain and serve as a novel classes of analgesics.

Impairment of spinal inhibitory input that gates central nociceptive circuits has been found to play a critical role underlying the facilitation of various chronic pain modalities. Specifically, several groups have shown that loss of balanced inhibitory/excitatory spinal neurotransmission either via disruption of neuronal chloride homeostasis and/or dysfunctional glycine-mediated fast synaptic inhibitory neurotransmission can enhance nociceptive drive resulting in mechanical hyperalgesia, allodynia and pathological pain. Maladaptive changes in spinal potassium-chloride cotransporter 2 (KCC2) expression results in diminished GABAergic and glycinergic signaling. Thus, potential novel analgesic strategies under investigation involve restoration of spinal inhibitory neurotransmission by enhancing KCC2-mediated chloride extrusion capacity via activation or increased expression of the transporter. Furthermore, drugs that selectively enhance dysfunctional glycinergic transmission in neuropathic pain, such as inhibitors of the glycine transporters (GlyTs) and glycine receptor (GlyR) positive allosteric modulators (PAMs), are generating widespread interest.

Submissions are welcome for the following article types: original research, review, mini-reviews, research protocol/method, opinion and hypothesis. We particularly welcome contributions that include, but are not limited to, the following topics:

1) The critical role that KCC2 plays in maintaining neuronal chloride homeostasis and how the loss of its chloride extrusion capacity has been shown to facilitate chronic pain states. Including pharmacological studies that demonstrate the potential promise that either activation or increased expression of KCC2 has toward re-establishing spinal inhibitory neurotransmission and treating pain.
2) The role that impaired inhibitory glycinergic function in the spinal dorsal horn plays in pathological pain states.
3) Recent advances toward the identification of glycine receptor (GlyR) positive allosteric modulators (PAMs) for the treatment of pain.
4) Development of glycine transporter inhibitors (GlyTs) as novel analgesics for the treatment of pain.