Differential effects of repeated low dose treatment with the cannabinoid agonist WIN 55,212-2 in experimental models of bone cancer pain and neuropathic pain.
Pain due to bone malignancies is one of the most difficult types of cancer pain to fully control and may further decrease the patients' quality of life. Animal models of chronic pain conditions resulting from peripheral inflammatory reactions or nerve injuries are responsive to treatment with cannabinoid agonists. However, the use of cannabinoid agonists in humans may be hampered by CNS related side effects and development of tolerance. In the present study, we investigated the effect of repeated low dose administration of the synthetic cannabinoid agonist WIN 55,212-2 on bone cancer pain and neuropathic pain in mice. In addition, we investigated the development of CNS related side effects and tolerance. We found that 0.5 mg/kg/day for 18 days reduced pain related behavior and expression of spinal glial fibrillary acidic protein in the bone cancer pain model but not in the neuropathic pain model. Furthermore, this treatment strategy was not found to induce measurable CNS related side effects or tolerance. Cancer cell viability assays and bone volume fraction assessed by micro computed tomography (microCT) demonstrated that these effects were not due to changes in cancer progression. The difference in WIN 55,212-2 efficacy between the bone cancer and neuropathic pain models may reflect the different pain generating mechanisms, which may be utilized in designing new therapeutic drugs.
Hald
Andreas
A
Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, Copenhagen University, Denmark.
Ding
Ming
M
Egerod
Kristoffer
K
Hansen
Rikke R
RR
Konradsen
Dorthe
D
Jørgensen
Stine G
SG
Atalay
Baris
B
Nasser
Arafat
A
Bjerrum
Ole J
OJ
Heegaard
Anne-Marie
AM
D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D048588:Benzoxazines / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000150:complications*; D063386:Cannabinoid Receptor Agonists; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005727:Ganglia, Spinal / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009025:Morpholines / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000150:complications*; D010812:Physical Stimulation; D004856:Postural Balance / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014057:Tomography, X-Ray Computed; D016474:Weight-Bearing / Q000502:physiology
D000700:Analgesics; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D005904:Glial Fibrillary Acidic Protein; 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; D012313:RNA