Studies in a rat model of cancer-induced bone pain : electrophysiology, pharmacology and behaviour
Cancer-induced bone pain (CIBP), resulting from primary sarcoma in the bone or metastatic spread to bone, is a common complaint among cancer patients and a major clinical problem. Recent innovations in rodent models of CIBP have facilitated investigation of novel drug treatments and of the mechanisms underlying this condition. The aim of this project was to characterize behavioural and dorsal horn neuronal alterations in a rat model of CIBP, and to study the effects of these alterations on different pharmacological systems. Following intratibial injection of MRMT1 mammary carcinoma cells to induce CIBP, behavioural testing revealed that cancer animals developed significant mechanical and cold allodynia, as well as ambulatory-evoked pain, commencing on post-operative day 9. Sham-operated animals (injection of cell medium alone) showed no behavioural alterations. In vivo electrophysiological characterization of superficial dorsal horn (SDH) neuronal responses to natural (mechanical, heat, brush and cold) and electrical stimuli in the halothane anaesthetized rat revealed neuropathological alterations correlating temporally with the behavioural alterations. There was a marked shift in SDH neuronal populations such that in shams the ratio of wide dynamic range (WDR) to nociceptive specific (NS) cells was 26%:74% whereas in animals with CIBP it was 47%:53%. Furthermore, WDR cells in animals with CIBP had significantly increased responses to mechanical, thermal, and electrical-evoked stimuli compared to shams. These first studies show that the spinal cord is hyperexcitable in CIBP, probably driven by changes in populations of SDH neurons, and that there is a clear temporal link between behavioural and neuronal alterations proving the latter to be a viable substrate for pharmacological testing in this pain model. Acute electrophysiological study using the selective 5-HT3 receptor antagonist ondansetron showed that descending facilitatory serotonergic pathways are enhanced in CIBP. Gabapentin and morphine worked both acutely and chronically to normalise the evoked dorsal horn neuronal responses in rats with CIBP. Chronic behavioural studies showed that these drugs also significantly reduced pain behaviour to the pre-operative baseline response and, furthermore, gabapentin shifted the abnormal WDR:NS SDH cell ratio back towards the sham ratio. These investigations therefore confirmed that pain behaviour in CIBP is strongly linked to changes in populations and excitability of SDH neurones, and highlighted gabapentin as a possible novel treatment for CIBP in the clinic.