Abstract P3-12-06: Subpopulations of peripheral sensory neurons are differentially sensitive to the microtubule-targeting agent, paclitaxel

Abstract

Abstract Paclitaxel (PTX), a microtubule-targeting anticancer agent, produces a debilitating peripheral neuropathy that is accompanied by neuropathic pain. Patients develop localized pain in their distal extremities, and more frequently complain of increased sensitivity to cold rather than hot temperatures. These clinical observations led us to hypothesize that PTX differentially damages subpopulations of peripheral sensory neurons. The purpose of this study was to evaluate the effects of PTX on bradykinin (BK) and eicosanoid (EP) receptor-expressing sensory neurons. PTX (11.7 mg/kg) or vehicle (Cremophor EL/EtOH/PBS; 1:1:6) was administered intraperitoneally to Sprague-Dawley rats (250-300 g) every other day for 5 days. Following treatment, PTX-treated rats exhibited increased sensitivity to cold and mechanical stimuli, but decreased sensitivity to heat stimulation as compared to vehicle-treated rats. Intraplantar (i.pl.) injection with BK (5 μg) produced a prolonged allodynia to cold, but a diminished allodynia to heat in PTX-treated rats. Interestingly, following treatment with PGE2 (0.3 μg, i.pl.), PTX-treated rats displayed no statistically significant differences in the allodynia to cold or heat compared to vehicle-treated rats. Efficacy of BK (1 pM - 1 μM) to stimulate inositol phosphate (IP) production in cultured primary sensory neurons from PTX-treated rats was significantly reduced. By contrast, stimulation of cAMP production by PGE2 (0.01 pM - 100 nM) was unaffected by PTX treatment. Preliminary mechanistic studies treating naïve cultures of rat primary sensory neurons directly with PTX (5 nM, 0 - 48 hr) yielded a time-dependent, tri-phasic effect on BK-stimulated IP accumulation and reduced PGE2-stimulated cAMP production, suggesting PTX differentially disrupts BK- and PGE2-mediated signaling. Collectively, these data provide evidence that subpopulations of peripheral sensory neurons are differentially sensitive to PTX. Understanding why particular subclasses are less sensitive, or resistant, to damage could reveal novel approaches to protect sensory neurons from chemotoxicity and ultimately prevent chemotherapy-induced peripheral neuropathy. Supported by USPS grant #8ULITR000149, Greehey Fellowship, and Translational Science Training Across Disciplines Program at UTHSCSA The project described was supported by Award Number 8UL1TR000149 from the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences. Citation Format: Peter M LoCoco, Teresa C Chavera, Raehannah J Jamshidi, Susan L Mooberry, Kelly A Berg, William P Clarke. Subpopulations of peripheral sensory neurons are differentially sensitive to the microtubule-targeting agent, paclitaxel [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-12-06.