| The negative impact cancer pain has on quality of life, particularly at the end stages of the disease, is profound. This thesis presents three distinct new models to study different aspects of cancer pain. It also defines unique mediators and relevant pharmacological and anatomical factors involved in these models.; Cancer pain presents clinically in several ways. These models facilitate investigation of pain arising from the primary tumor site (calcaneus implantation), secondary to the tumor site (femur implantation), and pain upon movement (bilateral humerus implantation). In the calcaneus and femur model, testing was done on the plantar surface of the ipsilateral paw. Progressive tumor-induced hyperalgesia was detected to mechanical and thermal (cold) stimulation, but not to heat, in both cases. In the humerus model, hyperalgesia was measured as a reduction in grip-force. In all models, the magnitude of hyperalgesia was enhanced by actual bone involvement, compared to implantation of tumors in adjacent sites.; Several tumor products involved in regulating growth, angiogenesis, or metastasis may also induce pain. We describe nociceptive characteristics of two of these, tumor necrosis factor-α (TNF-α) and endothelin (ET). TNF-α sensitized mice to mechanical stimulation, whereas ET-1 induced nocifensive behaviors. Intra-tumor injection of blockers of either algogen attenuated tumor-induced hyperalgesia, indicating their role in its production.; Visualization of the tumor-nerve interface was made possible by implanting DsRed2-transfected tumor cells. In vivo, the tumor was innervated with sensory nerve fibers, and the level of innervation correlated with hyperalgesia. Innervation of the tumor proper is evidence such that primary nociceptors may be exposed to tumor products. In addition, the density of vascularization correlated negatively with extent of hyperalgesia.; Morphine reversed hyperalgesic behaviors, confirming the idea that we are measuring nociception in these models. Additionally, systemic clonidine was more potent than and synergized with morphine. NSAIDs were ineffective and morphine 3-fold less potent in attenuating the movement-related hyperalgesia when compared to an inflammatory insult.; By developing and characterizing models of cancer pain, the potential for new analgesic testing and the ability to relate mechanistic correlates from in vitro work will bring forth better treatments for cancer pain in the future. |
