Involvement of peripheral adenosine 5'-triphosphate and P2X purinoceptor in pain-related behavior produced by orthotopic melanoma inoculation in mice.
Adenosine 5'-triphosphate (ATP) plays an important role in nociceptive processing. We used a mouse model of skin cancer pain to investigate the role of ATP in cancer pain. Orthotopic inoculation of B16-BL6 melanoma cells into the hind paw produced spontaneous licking of the tumor-bearing paw. Intraperitoneal injection of the P2 purinoceptor antagonist suramin suppressed spontaneous licking dose-dependently. Two P2X purinoceptor antagonists also suppressed spontaneous licking. An intraplantar injection of ATP, which did not induce licking in the healthy paw, increased licking of the tumor-bearing paw. Spontaneous firing of the tibial nerve was significantly increased in tumor-bearing mice and was inhibited by suramin. Extracellular concentration of ATP was significantly increased in the tumor-bearing paw than in the normal paw. ATP is concentrated in the culture medium of melanoma, lung cancer and breast cancer cells, but not fibroblasts. The P2X(3) receptor was expressed in about 40% of peripherin-positive small and medium-sized neurons in the dorsal root ganglia. P2X(3)-positive neurons were significantly increased in melanoma-bearing mice. These results suggest that ATP and P2X, especially P2X(3), receptors are involved in skin cancer pain, due to the increased release of ATP and increased expression of P2X(3) receptors in the sensory neurons.
Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
Masahide
M
Fujita
Tsugunobu
T
Andoh
Atsushi
A
Sasaki
Ikuo
I
Saiki
Yasushi
Y
Kuraishi
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000503:physiopathology; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058469:Receptors, Purinergic P2X; D058477:Receptors, Purinergic P2X3; D012878:Skin Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D013979:Tibial Nerve / Q000187:drug effects / Q000503:physiopathology
C546409:P2rx3 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D058477:Receptors, Purinergic P2X3; D000255:Adenosine Triphosphate