The stage specific plasticity of descending modulatory controls in a rodent model of cancer induced bone pain

Abstract

Pain resulting from metastatic bone disease is a major unmet clinical need. Studying spinal processing in rodent models of cancer pain is desirable since the percept of pain is influenced in part by modulation at the level of the transmission system in the dorsal horn of the spinal cord. Here a rodent model of cancer induced bone pain (CIBP) was generated following syngenic rat mammary gland adenocarcinoma cell injection in the tibia of male Sprague Dawley rats. Disease progression was classified as early or late stage according to bone destruction. Even though wakeful CIBP rats showed progressive mechanical hypersensitivity, subsequent in vivo electrophysiological measurement of mechanically evoked deep dorsal horn spinal neuronal responses revealed no change. Rather, a dynamic reorganization of spinal neuronal modulation by descending controls was observed, and this was maladaptive only in the early stage of CIBP. Interestingly, this latter observation corresponded with the degree of damage to the primary afferents innervating the cancerous tissue. Plasticity in the modulation of spinal neuronal activity by descending control pathways reveals a novel opportunity for targeting CIBP in a stage-specific manner. Finally, the data herein has translational potential since the descending control pathways measured are present also in man. Simple SummaryThe mechanisms that underlie pain resulting from metastatic bone disease remain elusive. This translates to a clinical and socioeconomic burden; targeted therapy is not possible, and patients do not receive adequate analgesic relief. Complicating matters is the heterogeneous nature of metastatic bone disease. Early stage cancers are molecularly very different to their late stage counterparts and so too is the pain associated with infant and advanced tumours. Thus, analgesic approaches should differ according to disease stage. In this article we demonstrate that a unique form of brain inhibitory control responsible for modulation of incoming pain signals at the level of the spinal cord changes with the progression of bone tumours, This corresponds with the degree of damage to the primary afferents innervating the cancerous tissue. Plasticity in the modulation of spinal neuronal activity by descending control pathways reveals a novel opportunity for targeting bone cancer pain in a stage-specific manner.