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Chemotherapy-induced peripheral neuropathic pain (CIPNP) often occurs in cancer patients treated with antineoplastic drugs. Therapeutic management of CIPNP is very limited, at least in part due to the largely unknown mechanisms that underlie CIPNP genesis. Here, we showed that systemic administration of the chemotherapeutic drug paclitaxel significantly and time-dependently increased the levels of cyclic AMP response element-binding protein (CREB) in dorsal root ganglion (DRG) neurons. Blocking this increase through DRG microinjection of Creb siRNA attenuated paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities. Mimicking this increase through DRG microinjection of the adeno-associated virus 5 expressing full-length Creb mRNA led to enhanced responses to basal mechanical, heat, and cold stimuli in mice in absence of paclitaxel treatment. Mechanically, paclitaxel-induced increase of DRG CREB protein augmented Dnmt3a promoter activity and participated in the paclitaxel-induced upregulation of DNMT3a protein in the DRG. CREB overexpression also elevated the expression of DNMT3a in in vivo and in vitro DRG neurons of naïve mice. Given that DNMT3a is an endogenous instigator of CIPNP and that CREB co-expresses with DNMT3a in DRG neurons, CREB may be a key player in CIPNP through transcriptional activation of the Dnmt3a gene in primary sensory neurons. CREB is thus a likely potential target for the therapeutic management of this disorder.

Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy-induced neuropathic pain. K 2p 1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time-dependently downregulates the expression of K 2p 1.1 mRNA and its coding K 2p 1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel-induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K 2p 1.1 mRNA is attributed to paclitaxel-induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel-induced the decrease of DRG K 2p 1.1 and mimicking this increase reduces DRG K 2p 1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K 2p 1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a-triggered downregulation of DRG K 2p 1.1 may contribute to chemotherapy-induced neuropathic pain., (© 2019 UICC.)

Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy‐induced neuropathic pain. K2p1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time‐dependently downregulates the expression of K2p1.1 mRNA and its coding K2p1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel‐induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K2p1.1 mRNA is attributed to paclitaxel‐induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel‐induced the decrease of DRG K2p1.1 and mimicking this increase reduces DRG K2p1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K2p1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a‐triggered downregulation of DRG K2p1.1 may contribute to chemotherapy‐induced neuropathic pain. What's new? Chemotherapy‐induced peripheral neuropathic pain (CIPNP) limits the dosage and selection of anti‐cancer drugs for patients and can lead to therapy discontinuation. While the mechanism underlying CIPNP remains unclear, two‐pore domain background potassium (K2p) channels, which influence neuronal activity, likely play a role. Here, in mice, systemic administration of paclitaxel was found to downregulate K2p1.1 in dorsal root ganglion (DRG) neurons. K2p1.1 knockdown, mimicking paclitaxel effects, resulted in reduced outward potassium channel current and increased DRG excitability. Elevated expression of the DNA methyltransferase DNMT3a contributed to DRG K2p1.1 downregulation, suggesting that both DNMT3a and DRG K2p1.1 are crucial to CIPNP development. [ABSTRACT FROM AUTHOR]