title: Released lipids regulate transient receptor potential channel (TRP)-dependent oral cancer pain.
abstract: BACKGROUND
  Pain in the head neck area is an early symptom in oral cancer, supporting the hypothesis that cancer cells control the activities of surrounding nociceptors at the site of the tumor. Several reports implicate TRPV1 and TRPA1 in cancer pain, although there is a large gap in knowledge since the mechanisms for tumor-induced activation of these TRP receptors are unknown. Interestingly, TRP-active lipids such as linoleic acid, arachidonic acid, hydroxyoctadecadienoic acid and hydroxyeicosatetraenoic acid are significantly elevated in the saliva of oral cancer patients compared to normal patients, supporting a possible linkage between these lipids and oral cancer pain. We therefore hypothesize that oral squamous cell carcinomas release certain lipids that activate TRPV1 and/or TRPA1 on sensory neurons, contributing to the development of oral cancer pain.
  
  
  METHODS
  Lipid extracts were made from conditioned media of three human oral squamous cell carcinoma (OSCC) cell lines as well as one normal human oral keratinocytes cell line. These were then injected intraplantarly into rat hindpaws to measure spontaneous nocifensive behavior, as well as thermal and mechanical allodynia. For interventional experiments, the animals were pretreated with AMG517 (TRPV1 antagonist) or HC030031 (TRPA1 antagonist) prior to extract injection.
  
  
  RESULTS
  These studies demonstrate that lipids released from the three OSCC cell lines, but not the normal cell line, were capable of producing significant spontaneous nocifensive behaviors, as well as thermal and mechanical allodynia. Notably each of the cell lines produced a different magnitude of response for each of three behavioral assays. Importantly, pre-treatment with a TRPVI antagonist blocked lipid-mediated nocifensive and thermal hypersensitivity, but not mechanical hypersensitivity. In addition, pre-treatment with a TRPA1 antagonist only reversed thermal hypersensitivity without affecting lipid-induced nocifensive behavior or mechanical allodynia.
  
  
  CONCLUSIONS
  These data reveal a novel mechanism for cancer pain and provide strong direction for future studies evaluating the cellular mechanism regulating the TRP-active lipids by OSCC tumors.
authors.affiliation: Department of Endodontics, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas, 78229, USA. ruparels@uthscsa.edu.
authors.forename: Shivani
authors.initials: S
authors.lastname: Ruparel
authors.affiliation: Department of Endodontics, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas, 78229, USA. bendeleMR@uthscsa.edu.
authors.forename: Michelle
authors.initials: M
authors.lastname: Bendele
authors.affiliation: Department of Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. furra@uthscsa.edu.
authors.forename: Ashley
authors.initials: A
authors.lastname: Wallace
authors.affiliation: Department of Physiology, University of Texas Health Science Center at San Antonio, Texas, USA. greend3@uthscsa.edu.
authors.forename: Dustin
authors.initials: D
authors.lastname: Green
mesh_terms: D000818:Animals; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids; D008297:Male; D009062:Mouth Neoplasms / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D008055:Lipids; D050916:TRPV Cation Channels