Inhibition of c-Kit signaling is associated with reduced heat and cold pain sensitivity in humans

• Published in: Pain (Amsterdam) Vol. 155; no. 7; pp. 1222 - 1228
• Main Authors: Ceko, Marta, Milenkovic, Nevena, le Coutre, Philipp, Westermann, Jörg, Lewin, Gary R.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier B.V 01.07.2014; International Association for the Study of Pain; Elsevier
• Subjects: Adult; Aged; Analgesia; Antineoplastic Agents - pharmacology; Benzamides - pharmacology; Biological and medical sciences; c-Kit; Case-Control Studies; Chronic myeloid leukemia; Cold pain; Cold Temperature; Female; Fundamental and applied biological sciences. Psychology; Heat pain; Hematologic and hematopoietic diseases; Hot Temperature; Humans; Imatinib; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Nilotinib; Nociception - drug effects; Nociception - physiology; Pain - metabolism; Pain Perception - drug effects; Pain Perception - physiology; Pain Threshold; Piperazines - pharmacology; Proto-Oncogene Proteins c-kit - antagonists & inhibitors; Proto-Oncogene Proteins c-kit - metabolism; Pyrimidines - pharmacology; Quantitative sensory testing; Signal Transduction; Skin - drug effects; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Tactile acuity; Vertebrates: nervous system and sense organs; Nilotinib; Analgesia; Imatinib; c-Kit; Cold pain; Chronic myeloid leukemia; Tactile acuity; Heat pain; Quantitative sensory testing; Human; Pain sensitivity; Temperature; Cold; Leukemia; Environmental factor; Malignant hemopathy; Tactile sensitivity; Signal transduction; Heat; Chronic; Pain; Perception; Inhibition; Cancer
• ISSN: 0304-3959; 1872-6623; 1872-6623
• DOI: 10.1016/j.pain.2014.03.010

The perception of painful stimuli is altered in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors such as Imatinib and Nilotinib. 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.