title: Inhibition of c-Kit signaling is associated with reduced heat and cold pain sensitivity in humans.
abstract: The tyrosine kinase receptor c-Kit is critically involved in the modulation of nociceptive sensitivity in mice. Ablation of the c-Kit gene results in hyposensitivity to thermal pain, whereas activation of c-Kit produces hypersensitivity to noxious heat, without altering sensitivity to innocuous mechanical stimuli. In this study, we investigated the role of c-Kit signaling in human pain perception. We hypothesized that subjects treated with Imatinib or Nilotinib, potent inhibitors of tyrosine kinases including c-Kit but also Abl1, PDFGFRα, and PDFGFRβ, that are used to treat chronic myeloid leukemia (CML), would experience changes in thermal pain sensitivity. We examined 31 asymptomatic CML patients (14 male and 17 female) receiving Imatinib/Nilotinib treatment and compared them to 39 age- and sex-matched healthy controls (12 male and 27 female). We used cutaneous heat and cold stimulation to test normal and noxious thermal sensitivity, and a grating orientation task to assess tactile acuity. Thermal pain thresholds were significantly increased in the Imatinib/Nilotinib-treated group, whereas innocuous thermal and tactile thresholds were unchanged compared to those in the control group. In conclusion, our findings suggest that the biological effects of c-Kit inhibition are comparable in mice and humans in that c-Kit activity is required to regulate thermal pain sensitivity but does not affect innocuous thermal and mechanical sensation. The effect on experimental heat pain observed in our study is comparable to those of several common analgesics; thus modulation of the c-Kit pathway can be used to specifically modulate noxious heat and cold sensitivity in humans.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany Department of Haematology, Oncology and Tumor Immunology, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Ceko
authors.forename: Nevena
authors.initials: N
authors.lastname: Milenkovic
authors.forename: Philipp
authors.initials: P
authors.lastname: le Coutre
authors.forename: Jörg
authors.initials: J
authors.lastname: Westermann
authors.forename: Gary R
authors.initials: GR
authors.lastname: Lewin
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D016022:Case-Control Studies; D003080:Cold Temperature; D005260:Female; D006358:Hot Temperature; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D059225:Nociception / Q000187:drug effects* / Q000502:physiology; D010146:Pain / Q000378:metabolism*; D058748:Pain Perception / Q000187:drug effects / Q000502:physiology; D017288:Pain Threshold; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C498826:nilotinib
keywords: Analgesia; Chronic myeloid leukemia; Cold pain; Heat pain; Imatinib; Nilotinib; Quantitative sensory testing; Tactile acuity; c-Kit