Paclitaxel induces acute pain via directly activating toll like receptor 4
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MOLECULAR PAIN
RESEARCH
Open Access
Paclitaxel induces acute pain via directly activating toll like receptor 4 Xisheng Yan1,2, Dylan W Maixner1, Ruchi Yadav1, Mei Gao1, Pei Li1, Michael G Bartlett1 and Han-Rong Weng1*
Abstract Paclitaxel, a powerful anti-neoplastic drug, often causes pathological pain, which significantly reduces the quality of life in patients. Paclitaxel-induced pain includes pain that occurs immediately after paclitaxel treatment (paclitaxel-associated acute pain syndrome, P-APS) and pain that persists for weeks to years after cessation of paclitaxel treatment (paclitaxel induced chronic neuropathic pain). Mechanisms underlying P-APS remain unknown. In this study, we found that paclitaxel causes acute pain in rodents in a dose-dependent manner. The paclitaxel-induced acute pain occurs within 2 hrs after a single intravenous injection of paclitaxel. This is accompanied by low levels of paclitaxel penetrating into the cerebral spinal fluid and spinal dorsal horn. We demonstrated that an intrathecal injection of paclitaxel induces mechanical allodynia in a dose-dependent manner. Paclitaxel causes activation of toll like receptor 4 (TLR4) in the spinal dorsal horn and dorsal root ganglions. Through activating TLR4, paclitaxel increases glutamatergic synaptic activities and reduces glial glutamate transporter activities in the dorsal horn. Activations of TLR4 are necessary in the genesis of paclitaxel-induced acute pain. The cellular and molecular signaling pathways revealed in this study could provide rationales for the development of analgesics and management strategies for P-APS in patients. Keywords: Taxol, Nociception, DRG, Neuroinflammation, EPSC, Burrowing behavior
Introduction Paclitaxel (taxol) is a first-line chemotherapeutic-agent used for the treatment of many types of cancers. Patients receiving taxol treatment often develop pathological pain, which significantly reduces their quality of life and hampers the use of this otherwise life-saving chemotherapy in the clinic. Pathological pain induced by taxol in patients includes pain that occurs immediately after taxol treatment (known as paclitaxel-associated acute pain syndrome, P-APS) [1,2], and pain that persists for weeks to years after cessation of paclitaxel treatment (known as paclitaxel induced chronic neuropathic pain) [3,4]. P-APS is a significant morbidity in patients [1,2]. Currently, there is no proven standard of care for the prevention or treatment of P-APS and mechanisms by which paclitaxel induces P-APS are not known. The current understanding of mechanisms underlying taxol-induced pathological pain in animal models is mainly based on studies that examine pathological changes days after * Correspondence: [email protected] 1 Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, 250 West Green Street, Athens 30602, GA, USA Full list of author information is available at the end of the article
cessation of repeated taxol treatments. Little is known about the direct and immediate
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