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.