CREB Participates in Paclitaxel-Induced Neuropathic Pain Genesis Through Transcriptional Activation of Dnmt3a in Primary Sensory Neurons

Abstract

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 timedependently 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.

A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABAA Receptor

“…Consistent with the previous reports [24,25], intraperitoneal (i.p.) injection of paclitaxel, but not vehicle 2, produced dramatic and long-lasting mechanical allodynia, heat hyperalgesia, and cold hyperalgesia on both sides in the vehicle 1-treated mice (Fig.…”

“…Paclitaxel-induced neuropathic pain model was carried out according to the protocol previously described [24,25]. Briefly, paclitaxel (4 mg/kg; dissolved in the vehicle) or vehicle (a mixture of ethanol and Cremophor EL (1:1)) was injected intraperitoneally every other day for 4 consecutive days (days 1, 3, 5, and 7; 16 mg/kg in total dose).…”

C/EBPβ Participates in Nerve Trauma-Induced TLR7 Upregulation in Primary Sensory Neurons

“…C/EBPβ belongs to the C/EBPs family with six members that have been reported, which are basic-leucine zipper transcription factors that interact with CCAAT motifs present in numerous gene promoters. Similar to TFs like myeloid zinc finger [28,29], octamer transcription factor 1 [24,36], and runt-related transcription factor 1 [21], C/EBPβ expression can be regulated following peripheral nerve trauma. A previous study revealed that CCI upregulated C/EBPβ expression at protein and mRNA levels in the ipsilateral L3/4 DRGs [17].…”

“…Behavioral testing was accomplished by one investigator who was blinded with the group. Five behavioral tests were carried out as described previously, including mechanical, thermal, and cold tests, in addition to locomotor activity and conditional place preference (CPP) tests [25][26][27][28]. Each evoked behavioral test was committed at 30-min intervals.…”

C/EBPβ Participates in Nerve Trauma-Induced TLR7 Upregulation in Primary Sensory Neurons

“…All behavioral testing was accomplished by one investigator who was blinded with the group. Five behavioral tests were carried out as described previously, including mechanical, thermal, and cold tests, in addition to locomotor activity and conditional place preference (CPP) tests [18][19][20][21]. Each evoked behavioral test was committed at 30 min intervals.…”