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Patients with metastatic breast, lung or prostate cancer frequently have significant bone cancer pain. In the present report we address, in a single in vivo mouse model, the effects the bisphosphonate alendronate has on bone cancer pain, bone remodeling and tumor growth and necrosis. Following injection and confinement of green fluorescent protein-transfected murine osteolytic tumor cells into the marrow space of the femur of male C3H/HeJ mice, alendronate was administered chronically from the time the tumor was established until the bone cancer pain became severe. Alendronate therapy reduced ongoing and movement-evoked bone cancer pain, bone destruction and the destruction of sensory nerve fibers that innervate the bone. Whereas, alendronate treatment did not change viable tumor burden, both tumor growth and tumor necrosis increased. These data emphasize that it is essential to utilize a model where pain, skeletal remodeling and tumor growth can be simultaneously assessed, as each of these can significantly impact patient quality of life and survival.

The phenotype of NK1R−/− mice was compared with that of acute pharmacological blockade of the tachykinin NK 1 receptor on sensorimotor function and in assays relevant to depressive illness and anxiety. The dose range for L-760735 and GR205171 that was associated with functional blockade of central NK 1 receptors in the target species was established by antagonism of the behavioural effects of intracerebroventricular NK 1 agonist challenge in gerbils, mice and rats. The caudal grooming and scratching response to GR73632 was absent in NK1R−/− mice, confirming that the receptor had been genetically ablated. There was no evidence of sedation or motor impairment in NK1R−/− mice or following administration of L-760735 to gerbils, even at doses in excess of those required for central NK 1 receptor occupancy. In the resident–intruder and forced swim test, the behaviour of NK1R−/− mice, or animals treated acutely with L-760735 or GR205171, resembled that seen with the clinically used antidepressant drug fluoxetine. However, the effects of GR205171 were not clearly enantioselective in mice. In contrast, although NK1R−/− mice also exhibited an increase in the duration of struggle behaviour in the tail suspension test, this was not observed following pharmacological blockade with L-760735 in gerbils or GR205171 in mice, suggesting that this may reflect a developmental alteration in the knockout mouse. There was no effect of NK 1 receptor blockade with L-760735 in guinea-pigs or GR205171 in rats, or deletion of the NK 1 receptor in mice, on behaviour in the elevated plus-maze test for anxiolytic activity. These findings extend previous observations on the phenotype of the NK1R−/− mouse and establish a broadly similar profile following acute pharmacological blockade of the receptor. These studies also serve to underscore the limitations of currently available antagonists that are suitable for use in rat and mouse behavioural assays.