Denis R. Clohisy

Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons.

The aim of this investigation was to determine whether murine models of inflammatory, neuropathic and cancer pain are each characterized by a unique set of neurochemical changes in the spinal cord and sensory neurons. All models were generated in C3H/HeJ mice and hyperalgesia and allodynia behaviorally characterized. A variety of neurochemical markers that have been implicated in the generation and maintenance of chronic pain were then examined in spinal cord and primary afferent neurons.Three days after injection of complete Freunds adjuvant into the hindpaw (a model of persistent inflammatory pain) increases in substance P, calcitonin gene-related peptide, protein kinase C gamma, and substance P receptor were observed in the spinal cord. Following sciatic nerve transection or L5 spinal nerve ligation (a model of persistent neuropathic pain) significant decreases in substance P and calcitonin gene-related peptide and increases in galanin and neuropeptide Y were observed in both primary afferent neurons and the spinal cord. In contrast, in a model of cancer pain induced by injection of osteolytic sarcoma cells into the femur, there were no detectable changes in any of these markers in either primary afferent neurons or the spinal cord. However, in this cancer-pain model, changes including massive astrocyte hypertrophy without neuronal loss, increase in the neuronal expression of c-Fos, and increase in the number of dynorphin-immunoreactive neurons were observed in the spinal cord, ipsilateral to the limb with cancer. These results indicate that a unique set of neurochemical changes occur with inflammatory, neuropathic and cancer pain in C3H/HeJ mice and further suggest that cancer induces a unique persistent pain state. Determining whether these neurochemical changes are involved in the generation and maintenance of each type of persistent pain may provide insight into the mechanisms that underlie each of these pain states.

Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord.

Bone cancer pain is common among cancer patients and can have a devastating effect on their quality of life. A chief problem in designing new therapies for bone cancer pain is that it is unclear what mechanisms drive this distinct pain condition. Here we show that osteoprotegerin, a secreted ‘decoy’ receptor that inhibits osteoclast activity, also blocks behaviors indicative of pain in mice with bone cancer. A substantial part of the actions of osteoprotegerin seems to result from inhibition of tumor-induced bone destruction that in turn inhibits the neurochemical changes in the spinal cord that are thought to be involved in the generation and maintenance of cancer pain. These results demonstrate that excessive tumor-induced bone destruction is involved in the generation of bone cancer pain and that osteoprotegerin may provide an effective treatment for this common human condition.

Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur

Although skeletal pain plays a major role in reducing the quality of life in patients suffering from osteoarthritis, Pagets disease, sickle cell anemia and bone cancer, little is known about the mechanisms that generate and maintain this pain. To define the peripheral fibers involved in transmitting and modulating skeletal pain, we used immunohistochemistry with antigen retrieval, confocal microscopy and three-dimensional image reconstruction of the bone to examine the sensory and sympathetic innervation of mineralized bone, bone marrow and periosteum of the normal mouse femur. Thinly myelinated and unmyelinated peptidergic sensory fibers were labeled with antibodies raised against calcitonin gene-related peptide (CGRP) and the unmyelinated, non-peptidergic sensory fibers were labeled with the isolectin B4 (Bandeira simplicifolia). Myelinated sensory fibers were labeled with an antibody raised against 200-kDa neurofilament H (clone RT-97). Sympathetic fibers were labeled with an antibody raised against tyrosine hydroxylase. CGRP, RT-97, and tyrosine hydroxylase immunoreactive fibers, but not isolectin B4 positive fibers, were present throughout the bone marrow, mineralized bone and the periosteum. While the periosteum is the most densely innervated tissue, when the total volume of each tissue is considered, the bone marrow receives the greatest total number of sensory and sympathetic fibers followed by mineralized bone and then periosteum. Understanding the sensory and sympathetic innervation of bone should provide a better understanding of the mechanisms that drive bone pain and aid in developing therapeutic strategies for treating skeletal pain.

Molecular mechanisms of cancer pain.

Pain is the most disruptive influence on the quality of life of cancer patients. Although significant advances are being made in cancer treatment and diagnosis, the basic neurobiology of cancer pain is poorly understood. New insights into these mechanisms are now arising from animal models, and have the potential to fundamentally change the way that cancer pain is controlled.

Efficacy of systemic morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs. inflammatory pain

&NA; Pain is the cancer related event that is most disruptive to the cancer patients quality of life. Although bone cancer pain is one of the most severe and common of the chronic pains that accompany breast, prostate and lung cancers, relatively little is known about the mechanisms that generate and maintain this pain. Recently, we developed a mouse model of bone cancer pain and 16 days following tumor implantation into the intramedullary space of the femur, significant bone destruction and bone cancer pain‐related behaviors were observed. A critical question is how closely this model mirrors human bone cancer pain. In the present study we show that, as in humans, pain‐related behaviors are diminished by systemic morphine administration in a dose dependent fashion that is naloxone‐reversible. Humans suffering from bone cancer pain generally require significantly higher doses of morphine as compared to individuals with inflammatory pain and in the mouse model, the doses of morphine required to block bone cancer pain‐related behaviors were ten times that required to block peak inflammatory pain behaviors of comparable magnitude induced by hindpaw injection of complete Freunds adjuvant (CFA) (1–3 mg/kg). As these animals were treated acutely, there was not time for morphine tolerance to develop and the rightward shift in analgesic efficacy observed in bone cancer pain vs. inflammatory pain suggests a fundamental difference in the underlying mechanisms that generate bone cancer vs. inflammatory pain. These results indicate that this model may be useful in defining drug therapies that are targeted for complex bone cancer pain syndromes.

Function and quality-of-life of survivors of pelvic and lower extremity osteosarcoma and Ewing's sarcoma: the Childhood Cancer Survivor Study

Limb-sparing surgeries have been performed more frequently than amputation based on the belief that limb-sparing surgeries provide improved function and quality-of-life (QOL). However, this has not been extensively studied in the paediatric population, which has unique characteristics that have implications for function and QOL. Using the Childhood Cancer Survivor Study, 528 adult long-term survivors of pediatric lower extremity bone tumours, diagnosed between 1970 and 1986, were contacted and completed questionnaries assessing function and QOL. Survivors were an average of 21 years from diagnosis with an average age of 35 years. Overall they reported excellent function and QOL. Compared to those who had a limb-sparing procedure, amputees were not more likely to have lower function and QOL scores and self-perception of disability included general health status, lower educational attainment, older age and female gender. Findings from this study suggest that, over time, amputees do as well as those who underwent limb-sparing surgeries between 1970 and 1986. However, female gender, lower educational attainment and older current age appear to influence function, QOL and disability.

Limb Salvage and Amputation in Survivors of Pediatric Lower-Extremity Bone Tumors: What Are the Long-Term Implications?

The past four decades have seen tremendous progress in the treatment of pediatric and adolescent cancers. As a consequence, there are increasing numbers of adult childhood cancer survivors. This has prompted investigation into the long-term consequences of cancer treatments. One group that merits special study is the survivors of lower-extremity bone tumors. Their function and quality of life may depend in part on both the surgery and the age at which it was performed. Comparisons between studies are difficult because small numbers of patients and the use of varying research designs and methods have limited research in this area. The purpose of this article is to review the major surgical approaches to lower-limb bone tumors and their impact on pediatric patients. The results show that survival is equivalent between amputation and limb salvage. Complications occur more frequently in limb salvage. The long-term outcomes of those undergoing amputation and limb salvage have not been found to be substantially different in regard to quality of life. In conclusion, prospective long-term follow-up of pediatric patients with lower-limb tumors is needed to (1) determine in a uniform manner the long-term complications, quality of life, and functionality of this population and describe differences within this patient population based on age at diagnosis and surgical procedure, (2) identify areas of concern that are amenable to intervention, and (3) provide clinicians and future patients a better understanding of the surgical options.

Fractures associated with neuropathic arthropathy in adults who have juvenile-onset diabetes

Eighteen patients, twenty-five to fifty-two years old, who had juvenile-onset diabetes, had neuropathic arthropathy and fractures at the ankle or tarsus, most of which were bilateral. After a minimum follow-up of one year, four patients could not walk and fourteen were dependent on orthoses. In nine patients, the lesions produced fixed skeletal deformities that caused severe malum perforans, which in three patients was so severe that a below-the-knee amputation had to be done. In patients who had bilateral lesions, when the extremity that was initially involved was prevented from bearing weight, involvement of the contralateral limb became evident after an average of 4.5 months, compared with an average of twelve months in the patients who were allowed weight-bearing on the extremity that was initially involved. Our current treatment protocol is non-weight-bearing immobilization of the involved extremity, and we recommend prophylactic immobilization of the contralateral extremity with a protective cast or orthosis. All of the patients who had this treatment regimen could walk; in contrast, of the eleven patients who were not so treated, four could not walk.

Cellular and neurochemical remodeling of the spinal cord in bone cancer pain

Publisher Summary This chapter discusses the cellular and neurochemical remodeling of the spinal cord in bone cancer pain. To determine the neurochemical mechanisms that give rise to cancer pain, a model of bone cancer pain that shares many similarities with human cancer bone pain is developed. Following development of the model, the chapter characterized the extent of cancer-induced bone destruction, the sensory innervation of the bone, and the animal behavior indicative of pain, and the neurochemical changes that occur in the spinal cord and primary afferent neurons that may be involved in the generation and maintenance of cancer pain. The unique neurochemical reorganization of the spinal cord in bone cancer is mirrored by the clinical experience that analgesics that are efficacious in the relief of inflammatory or neuropathic pain are frequently ineffective at relieving advanced bone cancer pain. Understanding the distinct neurochemical events that are involved in the generation and maintenance of different persistent pain states should provide a mechanistic approach for understanding and developing novel therapies for unique persistent pain states such as cancer pain.

Biology of Bone Cancer Pain

Bone cancer pain is a devastating manifestation of metastatic cancer. Unfortunately, current therapies can be ineffective, and when they are effective, the duration of the patients survival typically exceeds the duration of pain relief. New, mechanistically based therapies are desperately needed. Study of experimental animal models has provided insight into the mechanisms that drive bone cancer pain and provides an opportunity for developing targeted therapies. Mechanisms that drive bone cancer pain include tumor-directed osteoclast-mediated osteolysis, tumor cells themselves, tumor-induced nerve injury, stimulation of transient receptor potential vanilloid type 1 ion channel, endothelin A, and host cell production of nerve growth factor. Current and future therapies include external beam radiation, osteoclast-targeted inhibiting agents, anti-inflammatory drugs, transient receptor potential vanilloid type 1 antagonists, and antibody therapies that target nerve growth factor or tumor angiogenesis. It is likely that a combination of these therapies will be superior to any one therapy alone.