Abstract
Painful peripheral neuropathy is a common adverse effect of paclitaxel (PTX) treatment. To analyze the contribution of transient receptor potential vanilloid 1 (TRPV1) in the development of PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia, TRPV1 expression in the rat spinal cord was analyzed after intraperitoneal administration of 2 and 4 mg/kg PTX. PTX treatment increased the expression of TRPV1 protein in the spinal cord. Immunohistochemistry showed that PTX (4 mg/kg) treatment increased TRPV1 protein expression in the superficial layers of the spinal dorsal horn 14 days after treatment. Behavioral assessment using the paw withdrawal response showed that PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia after 14 days was significantly inhibited by oral or intrathecal administration of the TRPV1 antagonist AMG9810. We found that intrathecal administration of small interfering RNA (siRNA) to knock down TRPV1 protein expression in the spinal cord significantly decreased PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia. Together, these results demonstrate that TRPV1 receptor expression in spinal cord contributes, at least in part, to the development of PTX-induced painful peripheral neuropathy. TRPV1 receptor antagonists may be useful in the prevention and treatment of PTX-induced peripheral neuropathic pain.
Highlights
Chemotherapy-induced peripheral neuropathy occurs with several chemotherapeutic agents, such as cisplatin, oxaliplatin, vincristine, and paclitaxel
On day 14, the responses to 5 g von Frey filaments (vFF) stimulation with PTX treatment were further increased compared to vehicle treatment by 76.2% ± 9.6% (2 mg/kg) and 88.5% ± 8.9% (4 mg/kg) (p < 0.01) compared to vehicle treatment (24.2% ± 4.1%, Figure 1B)
We demonstrated that mechanical allodynia/hyperalgesia and thermal hyperalgesia were observed on day 14 after the start of 2 or 4 mg/kg PTX treatment, which was administered on four alternate days from days 0 to 6
Summary
Chemotherapy-induced peripheral neuropathy occurs with several chemotherapeutic agents, such as cisplatin, oxaliplatin, vincristine, and paclitaxel. PTX-induced acute neuropathy usually presents as painful sensory neuropathy, with numbness, tingling, mechanical allodynia, and burning sensations on the feet and hands or both [3,4,5,6]. 1 plays a crucial role in PTX-induced painful neuropathy. Rodent models of PTX-induced peripheral neuropathy were developed to elucidate the pain mechanisms caused by PTX treatment [7,8,9,10]. Neurophysiological and biochemical studies show that the activation and sensitization of nociceptors plays a key role in neuropathic pain behavior following PTX treatment [11,12,13]
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