Long March Toward Safe and Effective Analgesia by Enhancing Gene Expression of : First Steps Taken.

Low intraneuronal chloride in spinal cord dorsal horn pain relay neurons is critical for physiologic transmission of primary pain afferents because low intraneuronal chloride dictates whether GABA-ergic and glycin-ergic neurotransmission is inhibitory. If the neuronal chloride elevates to pathologic levels, then spinal cord primary pain relay becomes leaky and exhibits the behavioral hallmarks of pathologic pain, namely hypersensitivity and allodynia. Low chloride in spinal cord dorsal horn neurons is maintained by proper gene expression of and sustained physiologic function of the KCC2 chloride extruding electroneutral transporter. Peripheral nerve injury and other forms of neural injury evoke greatly diminished gene expression and subsequent corruption of inhibitory neurotransmission in the spinal cord dorsal horn, thus causing derailment of the gate function for pain. Here I review key discoveries that have helped us understand these fundamentals, and focus on recent insights relating to the discovery of gene expression enhancing compounds compound screens in neurons. One such study characterized the kinase inhibitor, kenpaullone, more in-depth, revealing its function as a robust and long-lasting analgesic in preclinical models of nerve injury and cancer bone pain, also elucidating its mechanism of action GSK3β inhibition, diminishing delta-catenin phosphorylation, and facilitating its nuclear transfer and subsequent enhancement of gene expression by de-repressing Kaiso epigenetic transcriptional regulator. Future directions re gene expression enhancement are discussed, namely combination with other analgesics and analgesic methods, such as spinal cord stimulation and electroacupuncture, gene therapy, and leveraging gene expression-enhancing nanomaterials.