Pain resulting from cancer profoundly contributes to the erosion of the patients' quality of life although cancer pain is often managed effectively with narcotics, the many undesirable side effects associated with these medications limit their use. The development of new and effective treatments for cancer pain is hampered by a paucity of knowledge about the basic neurobiological mechanisms underlying cancer pain. We have been involved in the development of an animal model of cancer pain that will allow rigorous exploration of underlying mechanisms and testing of specific hypotheses. In the proposed studies, a multidisciplinary approach using behavioral, electrophysiological and morphological methods will be used to investigate peripheral mechanisms of cancer pain using a newly developed murine model. Our preliminary studies show that tumor growth following subcutaneous implantation of osteolytic fibrosarcoma cells into the hindpaw results in mechanical hyperalgesia on the ipsilateral paw. We will investigate effects of tumor growth on excitability and morphoiogy of cutaneous nociceptors in skin overlying the tumor. In electrophysiological recordings, we will determine whether nociceptors are spontaneously active and exhibit greater responses to natural stimuli (mechanical, heat and cold). In addition, we will determine the role of tumor necrosis factor, endothelin-1 and nerve growth factor each of which are hypothesized to be secreted from the tumor, on tumor-evoked nociception and on excitability of nociceptors. We will also investigate whether the fibrosarcoma tumor increases neural innervation of the epidermis in skin overlying the tumor. Immunostainingand confocal microscopy will be used to image and quantify epidermal innervation. Since epidermal nerve fibers include nociceptors, tumor-evoked proliferation and enhanced excitability of these fibers may contribute to cancer pain. These studies will provide new information on functional interactions between tumors and peripheral nerve. Results may have a direct impact on the future development of novel medications for cancer pain that act peripherally at the tumor/nerve level.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA091007-03
Application #
6634039
Study Section
Special Emphasis Panel (ZRG1-IFCN-5 (07))
Program Officer
O'Mara, Ann M
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
3
Fiscal Year
2003
Total Cost
$230,984
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Psychiatry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Uhelski, Megan L; Gupta, Kalpna; Simone, Donald A (2017) Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis. Pain 158:1711-1722
Khasabov, S G; Simone, D A (2013) Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia. Neuroscience 250:151-65
Uhelski, M L; Cain, D M; Harding-Rose, C et al. (2013) The non-selective cannabinoid receptor agonist WIN 55,212-2 attenuates responses of C-fiber nociceptors in a murine model of cancer pain. Neuroscience 247:84-94
Boyette-Davis, Jessica A; Eng, Cathy; Wang, Xin S et al. (2012) Subclinical peripheral neuropathy is a common finding in colorectal cancer patients prior to chemotherapy. Clin Cancer Res 18:3180-7
Brink, Thaddeus S; Pacharinsak, Cholawat; Khasabov, Sergey G et al. (2012) Differential modulation of neurons in the rostral ventromedial medulla by neurokinin-1 receptors. J Neurophysiol 107:1210-21
Khasabov, S G; Brink, T S; Schupp, M et al. (2012) Changes in response properties of rostral ventromedial medulla neurons during prolonged inflammation: modulation by neurokinin-1 receptors. Neuroscience 224:235-48
Khasabova, Iryna A; Chandiramani, Anisha; Harding-Rose, Catherine et al. (2011) Increasing 2-arachidonoyl glycerol signaling in the periphery attenuates mechanical hyperalgesia in a model of bone cancer pain. Pharmacol Res 64:60-7
Hillery, Cheryl A; Kerstein, Patrick C; Vilceanu, Daniel et al. (2011) Transient receptor potential vanilloid 1 mediates pain in mice with severe sickle cell disease. Blood 118:3376-83
Simone, Donald A; Khasabov, Sergey G; Cain, David M et al. (2011) Changes in response properties of nociceptors and dorsal horn neurons in a murine model of cancer pain. Fiziol Zh 57:75-7
Khasabova, Iryna A; Gielissen, James; Chandiramani, Anisha et al. (2011) CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain. Behav Pharmacol 22:607-16

Showing the most recent 10 out of 29 publications