A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain.
Pain associated with cancer and chronic musculoskeletal disorders can be difficult to control. We used murine models of cancer and inflammatory muscle pain to examine whether the cannabinoid receptor agonist WIN55,212-2 reduces hyperalgesia originating in deep tissues. C3H/He mice were anesthetized and implanted with osteolytic NCTC clone 2472 cells into the humeri or injected with 4% carrageenan into the triceps muscles of both forelimbs. At the time of peak hyperalgesia, WIN55,212-2 (1-30mg/kg) or vehicle was administered intraperitoneally and forelimb grip force was measured 0.5-24h later. WIN55,212-2 produced time- and dose-related antihyperalgesia in both models. A 10mg/kg dose of WIN55,212-2 fully reversed carrageenan-evoked muscle hyperalgesia. However, 30mg/kg of WIN55,212-2 attenuated tumor-evoked hyperalgesia only approximately 50%. After controlling for the difference in magnitude of hyperalgesia between the two models, WIN55,212-2 was still more potent at reducing hyperalgesia in the inflammatory model. In the cancer pain model, the antihyperalgesic effect of WIN55,212-2 was partially blocked by pretreatment with the selective CB1 (SR141716A) but not the CB2 (SR144528) receptor antagonist. In contrast, both antagonists blocked antihyperalgesic effects of WIN55,212-2 on carrageenan-evoked muscle hyperalgesia. Catalepsy and loss of motor coordination, known side effects of cannabinoids, did not account for the antihyperalgesia produced by WIN55,212-2. These data show that cannabinoids attenuate deep tissue hyperalgesia produced by both cancer and inflammatory conditions. Interestingly, cannabinoids differentially modulated carrageenan- and tumor-evoked hyperalgesia in terms of potency and receptor subtypes involved suggesting that differences in underlying mechanisms may exist between these two models of deep tissue pain.
Department of Oral Science, School of Dentistry, University of Minnesota, Minneapolis, MN 55455-0217, USA.
Lois J
LJ
Kehl
Darryl T
DT
Hamamoto
Paul W
PW
Wacnik
Devin L
DL
Croft
Blake D
BD
Norsted
George L
GL
Wilcox
Donald A
DA
Simone
D000818:Animals; D048588:Benzoxazines; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D001892:Camphanes / Q000494:pharmacology; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D002351:Carrageenan / Q000494:pharmacology; D002375:Catalepsy / Q000188:drug therapy; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D018737:Hand Strength; D006811:Humerus; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009025:Morpholines / Q000008:administration & dosage / Q000627:therapeutic use*; D009220:Myositis / Q000188:drug therapy* / Q000209:etiology; D009281:Naphthalenes / Q000008:administration & dosage / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000150:complications*; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D010880:Piperidines / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000037:antagonists & inhibitors; D000077285:Rimonabant
D048588:Benzoxazines; D002121:Calcium Channel Blockers; D001892:Camphanes; D002186:Cannabinoids; D018492:Dopamine Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C110630:SR 144528; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D002351:Carrageenan; D006220:Haloperidol; D000077285:Rimonabant