TET1 overexpression attenuates paclitaxel-induced neuropathic pain through rescuing K2p1.1 expression in primary sensory neurons of male rats.

AIMS: Paclitaxel-induced downregulation of two-pore domain K+ channel 1.1 (K2p1.1) caused by increasing DNA methylation within its gene promoter in the dorsal root ganglion (DRG) contributes to neuropathic pain. Given that ten-eleven translocation methylcytosine dioxygenase 1 (TET1) promotes DNA demethylation and gene transcription, the present study investigated whether DRG overexpression of TET1 produces an antinociceptive effect on the paclitaxel-induced nociceptive hypersensitivity. MAIN METHODS: TET1 was overexpressed in the DRG through unilateral microinjection of the herpes simplex virus expressing full-length Tet1 mRNA into the fourth and fifth lumbar DRGs of male rats. Behavioral tests were carried out to examine the effect of this overexpression on the paclitaxel-induced nociceptive hypersensitivity. Western blot analysis, chromatin immunoprecipitation assay and 5-hydroxymethylcytosine detection assay were performed to assess the levels of TET1/K2p1.1, 5-methylcytosine and 5-hydroxymethylcytosine, respectively. KEY FINDINGS: DRG overexpression of TET1 mitigated the paclitaxel-induced mechanical allodynia, heat hyperalgesia and cold hyperalgesia on the ipsilateral side during the development and maintenance periods. Locomotor function or basal (acute) responses to mechanical, heat or cold stimuli were not affected. Mechanistically, DRG overexpression of TET1 rescued the expression of K2p1.1 by blocking the paclitaxel-induced increase in the level of 5-methylcytosine and correspondingly reversing the paclitaxel-induced decreases in the amount of 5-hydroxymethylcytosine within the K2p1.1 promoter region in the microinjected DRGs of male rats. SIGNIFICANCE: Our findings suggest that DRG overexpression of TET1 alleviated chemotherapy-induced neuropathic pain likely through rescuing DRG K2p1.1 expression. Our findings may provide a potential avenue for the management of this disorder.

Exploring Pharmacological Functions of Alternatively Spliced Variants of the Mu Opioid Receptor Gene, Oprm1, via Gene-Targeted Animal Models.

The mu opioid receptor has a distinct place in the opioid receptor family, since it mediates the actions of most opioids used clinically (e.g., morphine and fentanyl), as well as drugs of abuse (e.g., heroin). The single-copy mu opioid receptor gene, OPRM1, goes through extensive alternative pre-mRNA splicing to generate numerous splice variants that are conserved from rodents to humans. These OPRM1 splice variants can be classified into three structurally distinct types: (1) full-length 7 transmembrane (TM) carboxyl (C)-terminal variants; (2) truncated 6TM variants; and (3) single TM variants. Distinct pharmacological functions of these splice variants have been demonstrated by both in vitro and in vivo studies, particularly by using several unique gene-targeted mouse models. These studies provide new insights into our understanding of the complex actions of mu opioids with regard to OPRM1 alternative splicing. This review provides an overview of the studies that used these gene-targeted mouse models for exploring the functional importance of Oprm1 splice variants.

A Case Report of High Cervical Spinal Cord Stimulation for Chronic Otalgia and Tinnitus.

Neuromodulation continues to grow in its scope and application in the relief of chronic and debilitating disorders. Both otalgia and tinnitus can be multifactorial in etiology, with diagnostic and treatment challenges. This is a case of spinal cord stimulator placement providing a patient with near total relief of otalgia, total relief of tinnitus, and mild improvement in sensorineural hearing loss. We believe that this is the first report showing benefit of high spinal cord stimulation in tinnitus, and we consider whether there are neuronal connections between upper cervical nerve roots and the auditory pathways.