AUTHOR=Yeo Michele , Zhang Qiaojuan , Ding LeAnne , Shen Xiangjun , Chen Yong , Liedtke Wolfgang 

TITLE=Spinal cord dorsal horn sensory gate in preclinical models of chemotherapy-induced painful neuropathy and contact dermatitis chronic itch becomes less leaky with Kcc2 gene expression-enhancing treatments

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 15 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.911606

DOI=10.3389/fnmol.2022.911606

ISSN=1662-5099

ABSTRACT=Low intraneuronal chloride in spinal cord dorsal horn (SCDH) pain relay neurons is of critical relevance for physiologic transmission of primary sensory afferents because low intraneuronal chloride dictates GABA-ergic and glycin-ergic neurotransmission to be inhibitory. In case neuronal chloride elevates to unphysiological levels, then the primary sensory gate in the spinal cord dorsal horn becomes corrupted with resulting behavioral hallmarks of hypersensitivity and allodynia, for example in pathologic pain.  Low chloride in spinal cord dorsal horn neurons relies on robust gene expression of Kcc2 and sustained transporter function of the KCC2 chloride-extruding electroneutral transporter. Based on a recent report where we characterized the GSK3-inhibitory small molecule, kenpaullone, as a Kcc2 gene expression-enhancer that potently repaired diminished Kcc2 expression and KCC2 transporter function in SCDH pain relay neurons, we extend our recent findings by reporting (i) effective pain control in a preclinical model of taxol-induced painful peripheral neuropathy that was accomplished by topical application of a TRPV4/TRPA1 dual-inhibitory compound (compound 16-8), and was associated with repair of diminished Kcc2 gene expression in the SCDH; (ii) kenpaullone functioned potently as antipruritic in a DNFB contact dermatitis preclinical model. These observations suggest that effective peripheral treatment of chemotherapy-induced painful peripheral neuropathy impacts the pain-transmitting neural circuit in the SCDH in a beneficial manner by enhancing Kcc2 gene expression, and that chronic pruritus might be relayed in the primary sensory gate of the spinal cord, following similar principles as pathologic pain, specifically relating to critical functioning of Kcc2 gene expression and KCC2 transporter function.