Background

The transcriptional repressor positive regulatory domain I–binding factor 1 (PRDM1) is expressed in adult mouse dorsal root ganglion and regulates the formation and function of peripheral sensory neurons. The authors hypothesized that PRDM1 in the dorsal root ganglion may contribute to peripheral nerve injury–induced nociception regulation and that its mechanism may involve Kv4.3 channel transcriptional repression.

Methods

Nociception was induced in C57BL/6 mice by applying chronic constriction injury, complete Freund’s adjuvant, or capsaicin plantar injection. Nociceptive response was evaluated by mechanical allodynia, thermal hyperalgesia, cold hyperalgesia, or gait analysis. The role of PRDM1 was evaluated by injection of Prdm1 knockdown and overexpression adeno-associated viruses. The interaction of PRDM1 at the Kv4.3 (Kcnd3) promoter was evaluated by chromatin immunoprecipitation assay. Excitability of dorsal root ganglion neurons was evaluated by whole cell patch clamp recordings, and calcium signaling in spinal dorsal horn neurons was evaluated by in vivo two-photon imaging.

Results

Peripheral nerve injury increased PRDM1 expression in the dorsal root ganglion, which reduced the activity of the Kv4.3 promoter and repressed Kv4.3 channel expression (injured vs. uninjured; all P < 0.001). Knockdown of PRDM1 rescued Kv4.3 expression, reduced the high excitability of injured dorsal root ganglion neurons, and alleviated peripheral nerve injury–induced nociception (short hairpin RNA vs. Scram; all P < 0.05). In contrast, PRDM1 overexpression in naive mouse dorsal root ganglion neurons diminished Kv4.3 channel expression and induced hyperalgesia (PRDM1 overexpression vs. control, mean ± SD; n = 13; all P < 0.0001) as evaluated by mechanical allodynia (0.6 ± 0.3 vs. 1.2 ± 0.2 g), thermal hyperalgesia (5.2 ± 1.3 vs. 9.8 ± 1.7 s), and cold hyperalgesia (3.4 ± 0.5 vs. 5.3 ± 0.6 s). Finally, PRDM1 downregulation in naive mice reduced the calcium signaling response of spinal dorsal horn neurons to thermal stimulation.

Conclusions

PRDM1 contributes to peripheral nerve injury–induced nociception by repressing Kv4.3 channel expression in injured dorsal root ganglion neurons.

Editor’s Perspective
What We Already Know about This Topic
  • The hyperexcitability of sensory neurons contributes to chronic pain after nerve injury

  • The diminished expression of membrane-stabilizing potassium ion channels contributes to this hyperexcitability

What This Article Tells Us That Is New
  • After nerve injury in mice, the enhanced expression of the positive regulatory domain I–binding factor 1 (PRDM1) reduced the expression of the Kv4.3 potassium ion channel

  • The reduced expression of Kv4.3 caused nociceptive sensitization in male and female mice

  • Conversely, maneuvers that enhanced Kv4.3 expression reduced nociceptive sensitivity in mice, suggesting that this regulatory pathway may have central importance in pain after nerve injury

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