Neurochemical and Cellular Reorganization of the Spinal Cord in a Murine Model of Bone Cancer Pain

Abstract

The cancer-related event that is most disruptive to the cancer patient's quality of life is pain. To begin to define the mechanisms that give rise to cancer pain, we examined the neurochemical changes that occur in the spinal cord and associated dorsal root ganglia in a murine model of bone cancer. Twenty-one days after intramedullary injection of osteolytic sarcoma cells into the femur, there was extensive bone destruction and invasion of the tumor into the periosteum, similar to that found in patients with osteolytic bone cancer. In the spinal cord, ipsilateral to the cancerous bone, there was a massive astrocyte hypertrophy without neuronal loss, an expression of dynorphin and c-Fos protein in neurons in the deep laminae of the dorsal horn. Additionally, normally non-noxious palpation of the bone with cancer induced behaviors indicative of pain, the internalization of the substance P receptor, and c-Fos expression in lamina I neurons. The alterations in the neurochemistry of the spinal cord and the sensitization of primary afferents were positively correlated with the extent of bone destruction and the growth of the tumor. This "neurochemical signature" of bone cancer pain appears unique when compared to changes that occur in persistent inflammatory or neuropathic pain states. Understanding the mechanisms by which the cancer cells induce this neurochemical reorganization may provide insight into peripheral factors that drive spinal cord plasticity and in the development of more effective treatments for cancer pain.

Regional Anesthesia and Pain

“…17 It has been reported that systemic administration of morphine produces an analgesic effect in this model, although the potency of morphine appears to be lower in the bone cancer pain model compared to the inflammatory pain model. 18,19 This suggests the existence of a different mechanism underlying bone cancer pain vs inflammatory pain.…”

“…This strain was chosen for its histocompatibility with the NCTC 2472 tumor line (American Type Culture Collection (ATCC), Rockville, MD, USA). A tumour cell injection protocol was performed as described previously by Schwei et al 17 Tumour cells, 10 5 in 20 µl of α minimal essential medium (αMEM, Sigma, St. Louis, MO, USA) containing 1% bovine serum albumin were injected directly into the medullary cavity of the distal femur under pentobarbital anesthesia.…”

Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain

“…Neurochemical and morphological rearrangement of the spinal cord are well known to be present in animal models of chronic pain (20)(21)(22)(23) and functional changes have been previously described in association with pain in primary somatosensory cortex (24) as well as in the anterior cingulate cortex, where up-regulation of NMDA NR2B subunits after peripheral inflammation has been recently shown (15). To our knowledge, however, morphological changes associated with pain have been described.…”

Effect of peptidases on the ability of exogenous and endogenous neurokinins to produce neurokinin 1 receptor internalization in the rat spinal cord

“…The amount of NK1R internalization was quantified using a standard method (Mantyh et al, 1995;Abbadie et al, 1997;Honore et al, 1999;Schwei et al, 1999;Trafton et al, 1999; with minor modifications (Marvizon et al, 1997;1999a). Briefly, we determined the percentage of NK1R immunoreactive neurons in lamina I that show internalization in relation to the total number of NK1R neurons sampled.…”