Local Loperamide Inhibits Thermal Hyperalgesia But Not Mechanical Allodynia Induced by Intratibial Inoculation of Melanoma Cells in Mice

The stimulation of peripheral opioid receptors counteracts thermal hyperalgesia produced by the intratibial inoculation of NCTC 2472 cells in mice, through the activation of the nitric oxide/cGMP/ATP-sensitive K⁺-channels (NO/cGMP/K⁺ _ATP) cascade (Menéndez et al. 2007, Neuropharmacology 53:71–80). We aimed to elucidate whether this peripheral opioid antihyperalgesic effect is exclusive to this model or might also occur in other types of bone neoplastic processes. In C57BL/6 mice intratibially inoculated with B16-F10 melanoma cells, the progressive tumoral damage was accompanied by the establishment of thermal hyperalgesia (unilateral hot plate test) and mechanical allodynia (von Frey test). Intraplantar administration of loperamide (15 μg, 30 min before) inhibited thermal hyperalgesia, but did not modify the intense mechanical allodynia. The fact that the coadministration of naloxone-methiodide (5 μg) completely suppressed the thermal antihyperalgesic effect induced by loperamide indicates its production through the stimulation of peripheral opioid receptors. Furthermore, its prevention by the coadministration of the non-selective inhibitor of the NO synthase, N^G-monomethyl-L-arginine (L-NMMA, 10 μg), the selective inhibitor of neural NOS, N-ω-propyl-L-arginine (1–10 μg), or the K⁺ _ATP channel blocker, glibenclamide (10 μg) demonstrated the involvement of the NO/cGMP/K⁺ _ATP pathway in the antihyperalgesic effect induced by loperamide. Overall, the present results show that the intratibial inoculation of B16-F10 cells to C57BL/6 mice evokes thermal hyperalgesia and mechanical allodynia and that, as occurred in the osteosarcoma model, the stimulation of peripheral opioid receptors is not effective in modifying neoplastic allodynia but completely inhibits thermal hyperalgesia through the activation of the NO/cGMP/K⁺ _ATP cascade.