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The Journal of Neuroscience, October 29, 2008, 28(44):11141-11152; doi:10.1523/JNEUROSCI.2847-08.2008

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Neurobiology of Disease
A Decrease in Anandamide Signaling Contributes to the Maintenance of Cutaneous Mechanical Hyperalgesia in a Model of Bone Cancer Pain

Iryna A. Khasabova,¹ Sergey G. Khasabov,¹ Catherine Harding-Rose,¹ Lia G. Coicou,² Bryan A. Seybold,² Amy E. Lindberg,³ Christopher D. Steevens,¹ Donald A. Simone,¹ and Virginia S. Seybold²

Departments of ¹Diagnostic/Biological Sciences and ²Neuroscience, and ³Pharmacology Graduate Program, University of Minnesota, Minneapolis, Minnesota 55455

Correspondence should be addressed to Dr. Virginia S. Seybold, Department of Neuroscience, University of Minnesota, 6-145 Jackson Hall, 321 Church Street, S.E., Minneapolis, MN 55455. Email: vseybold{at}umn.edu

Tumors in bone are associated with pain in humans. Data generated in a murine model of bone cancer pain suggest that a disturbance of local endocannabinoid signaling contributes to the pain. When tumors formed after injection of osteolytic fibrosarcoma cells into the calcaneus bone of mice, cutaneous mechanical hyperalgesia was associated with a decrease in the level of anandamide (AEA) in plantar paw skin ipsilateral to tumors. The decrease in AEA occurred in conjunction with increased degradation of AEA by fatty acid amide hydrolase (FAAH). Intraplantar injection of AEA reduced the hyperalgesia, and intraplantar injection of URB597, an inhibitor of FAAH, increased the local level of AEA and also reduced hyperalgesia. An increase in FAAH mRNA and enzyme activity in dorsal root ganglia (DRG) L3–L5 ipsilateral to the affected paw suggests DRG neurons contribute to the increased FAAH activity in skin in tumor-bearing mice. Importantly, the anti-hyperalgesic effects of AEA and URB597 were blocked by a CB1 receptor antagonist. Increased expression of CB1 receptors by DRG neurons ipsilateral to tumor-bearing limbs may contribute to the anti-hyperalgesic effect of elevated AEA levels. Furthermore, CB1 receptor protein-immunoreactivity as well as inhibitory effects of AEA and URB597 on the depolarization-evoked Ca²⁺ transient were increased in small DRG neurons cocultured with fibrosarcoma cells indicating that fibrosarcoma cells are sufficient to evoke phenotypic changes in AEA signaling in DRG neurons. Together, the data provide evidence that manipulation of peripheral endocannabinoid signaling is a promising strategy for the management of bone cancer pain.

Key words: cannabinoid; CB1 receptor; dorsal root ganglion (Drg); hyperalgesia; mice; skin; culture

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Received June 19, 2008; revised Sept. 16, 2008; accepted Sept. 22, 2008.

Correspondence should be addressed to Dr. Virginia S. Seybold, Department of Neuroscience, University of Minnesota, 6-145 Jackson Hall, 321 Church Street, S.E., Minneapolis, MN 55455. Email: vseybold{at}umn.edu

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