Brain -derived neurotrophic factor modulates paclitaxel-induced allodynia in the mouse

Abstract

Paclitaxel is one of the most commonly and widely prescribed chemotherapy agents used to treat cancers of the breast, ovaries, and lung. As many as 95% of paclitaxel treated patients, depending on their treatment protocol, develop painful and often disabling peripheral sensory complaints, which are generally resistant to both prevention and conventional approaches to symptom management. One in five patients survives paclitaxel treatment with persistent pain that limits quality of life. Brain-derived neurotrophic factor (BDNF), a growth factor critical to neuron development and survival, is implicated in the development of several neuropathic pain states but has not been examined as a potential mechanism responsible for the pain and sensory complaints that follow paclitaxel treatment. This study explored the potential nociceptive role of BDNF in a mouse model of paclitaxel-induced painful peripheral neuropathy, with a focus on the expression of BDNF and its receptor trkB in mechanical allodynia in the spinal cord. Serial doses of 1 mg/kg paclitaxel in a cremophor base (4 mg/kg cumulative dose) produced a mechanical allodynia in mice that persisted nearly 3 months after paclitaxel dosing ends. Allodynia was attenuated through experimental manipulation of the levels of BDNF ligand as well as through experimental manipulation of trkB isoform expression. Using mice producing less endogenous systemic BDNF we demonstrated that a reduction in paclitaxel-induced allodynia was associated with a reduction in BDNF expression, although the trajectory of symptom development following paclitaxel treatment remained unaltered. However, targeted reductions of spinal BDNF using an intrathecal BDNF scavenging protein reduced both allodynia development and the trajectory of symptom development, suggesting that BDNF modulates allodynia in a time and dose dependent manner. Moreover, genetic deletion of the truncated trkB.T1 receptor resulted in almost complete attenuation of paclitaxel-induced mechanical allodynia, while blockade of full-length trkB signaling blunted both the induction and the persistence of paclitaxel-induced nociception, suggesting that the truncated trkB isoform plays a critical role in paclitaxel-induced allodynia separate from the full length trkB receptor. Findings from this study have important implications for understanding both the neuropathic symptoms of mechanical allodynia as well as the specific mechanical hypersensitivity that follows paclitaxel administration. Results suggest that reducing levels of spinal BDNF early in the course of treatment many blunt both the severity and persistence of painful sensory symptoms, while therapies targeted at the truncated T1 isoform of the trkB receptor may reduce or prevent symptom onset.