Background & Aims
Cancer patients undergoing treatment with antineoplastic drugs often experience chemotherapy-induced neuropathic pain (CINP). Unfortunately, the therapeutic options for managing CINP are very limited, at least in part due to unclear mechanisms underlying this disorder. Neurotrophin-3 (NT3), a member of the nerve growth factor family of neurotrophins, is an important regulator of several physiological and pathologic processes. However, its role in nerve trauma-induced neuropathic pain is still elusive. The expression and function of NT3 in the dorsal root ganglion (DRG) under the conditions of CINP are unknown.
Methods
CINP was induced by intraperitoneal administration of paclitaxel at a dose of 4 mg/kg every other day for 8 consecutive days. To knockdown NT3 expression in the DRG, Nt3 short interfering RNA (Nt3 siRNA) and the sensory neuron-specific inducible conditional Nt3 knockdown mice (Nt3 cKD mice) were used. To overexpress NT3 in DRG, the adeno-associated virus 5 expressing full-length Nt3 mRNA (AAV5-NT3) was microinjected into unilateral L3/4 DRGs. Mechanical, heat, and cold behavioral tests aas well as conditional place preference testing were conducted prior to paclitaxel injection and on different days after paclitaxel injection. Quantitative real-time RT-PCR and Westen blot assays were carried out to examine the change of Nt3 mRNA and NT3 protein, respectively, in the DRG and spinal cord after paclitaxel injection. In situ hybridization histochemistry assay was performed to examine distribution pattern of Nt3 mRNA-positive neurons and their changes after paclitaxel injection in the DRG.
Results
systemic administration of paclitaxel significantly and time-dependently upregulated the expression of Nt3 mRNA and its coding NT3 protein in the neurons of DRG, but not in spinal cord. This upregulation was occurred exclusively in DRG neurons. Blocking this upregulation through microinjection of Nt3 siRNA into unilateral L3/4 DRGs or tamoxifen injection in Nt3 cKD mice attenuated paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities and spontaneous pain without altering acute pain and locomotor activity in both male and female mice. Conversely. mimicking this increase through DRG microinjection of AAV5-NT3 led to enhanced responses to mechanical, heat, and cold stimuli and spontaneous pain in naïve male and female mice. Mechanically, DRG upregulated NT3 protein triggered TrkC receptor activation and participated in the paclitaxel-induced increases of C-C chemokine ligand 2 (Ccl2) mRNA and its coding CCL2 protein in the DRG.
Conclusions
Given that CCL2 is an endogenous initiator of CINP and that Nt3 mRNA co-expresses with TrkC and Ccl2 mRNAs in DRG neurons, DRG upregulated NT3 likely contributes to CINP through the TrkC-mediated activation of Ccl2 gene in DRG neurons. NT3 may be a new potential target for CINP management.
References
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Presenting Author
Yuan-Xiang Tao
Poster Authors
Yuan-Xiang Tao
MD, PhD
Rutgers New Jersey Medical Sch
Lead Author
Dilip Sharma
Rutgers New Jersey Medical School
Lead Author
Xiaozhou Feng
Rutgers New Jersey Medical School
Lead Author
Bing Wang
Rutgers New Jersey Medical School
Lead Author
Huijuan Hu
Rutgers New Jersey Medical School
Lead Author
Topics
- Models: Chronic Pain - Neuropathic