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

Abstract

Aims: Paclitaxel-induced downregulation of two-pore domain K+ channel 1.1 (K_2p1.1) 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/K_2p1.1, 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 K_2p1.1 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 K_2p1.1 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 K_2p1.1 expression. Our findings may provide a potential avenue for the management of this disorder.

Keywords: Chemotherapy-induced neuropathic pain; DNA methylation; Dorsal root ganglion; K(2p) 1.1; Paclitaxel; TET1.