title: The non-selective cannabinoid receptor agonist WIN 55,212-2 attenuates responses of C-fiber nociceptors in a murine model of cancer pain.
abstract: Pain from cancer can be severe, difficult to treat, and greatly diminishes patients' quality of life. It is therefore important to gain new information on the mechanisms of cancer pain and develop new treatment strategies. We have used a murine model of bone cancer pain to investigate underlying peripheral neural mechanisms and novel treatment approaches. In this model, implantation of fibrosarcoma cells into and around the calcaneous bone produces mechanical and thermal hyperalgesia in mice. C-fiber nociceptors in tumor-bearing mice develop spontaneous ongoing activity and sensitization to thermal stimuli. However, it is unclear whether sensitization of nociceptors to mechanical stimuli underlies the mechanical hyperalgesia seen in tumor-bearing mice. We therefore examined responses of C-fiber nociceptors to suprathreshold mechanical stimuli in tumor-bearing mice and found they did not differ from those of C-nociceptors in control mice. Thus, sensitization of C-fiber nociceptors to mechanical stimulation does not appear to underlie tumor-evoked mechanical hyperalgesia in this murine model of bone cancer pain. We also examined the effect of the non-selective cannabinoid receptor agonist, WIN 55,212-2, on spontaneous activity and responses evoked by mechanical stimuli of C-fiber nociceptors innervating the tumor-bearing paw. Selective CB1 and CB2 antagonists were administered to determine the contribution of each receptor subtype to the effects of WIN 55,212-2. Intraplantar administration of WIN 55,212-2 attenuated spontaneous discharge and responses evoked by mechanical stimulation of C-fiber nociceptors. These effects were inhibited by prior intraplantar administration of selective CB1 (AM281) or CB2 (AM630) receptor antagonists but not by vehicle. These results indicate that activation of either CB1 or CB2 receptors reduced the spontaneous activity of C-fiber nociceptors associated with tumor growth as well as their evoked responses. Our results provide further evidence that activation of peripheral cannabinoid receptors may be a useful target for the treatment of cancer pain.
authors.affiliation: Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN 55447, United States.
authors.forename: M L
authors.initials: ML
authors.lastname: Uhelski
authors.forename: D M
authors.initials: DM
authors.lastname: Cain
authors.forename: C
authors.initials: C
authors.lastname: Harding-Rose
authors.forename: D A
authors.initials: DA
authors.lastname: Simone
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects* / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy* / Q000473:pathology
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
keywords: AM281; AM630; ANOVA; C-mechanoheat nociceptors; C-mechanonociceptors; CM; CMH; CV; DRG; IQR; PBS; PID; TRP; TRP ankyrin 1; TRP vanilloid 1; TRPA1; TRPV1; analysis of variance; conduction velocity; dorsal root ganglion; electrophysiology; interquartile range; mouse; peripheral nerve; phosphate-buffered saline; post-implantation day; tibial nerve; transient receptor potential