A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats.
Paclitaxel is an effective antineoplastic drug treatment used as an anti-tumoral therapy. Unfortunately its use is associated with unwanted side effects, which include the development of peripheral neuropathies and neuropathic pain, greatly affecting the quality of life of patients. It is well known that agonists of the cannabinoid receptor are able to reduce hyperalgesia and allodynia that develop after nerve injury. Our aim was to evaluate the efficacy of the cannabinoid agonist WIN 55,212-2 to reduce the thermal hyperalgesia and the tactile allodynia induced by administration of paclitaxel in rats. Present results demonstrate that WIN 55,212-2 (1 mg/kg i.p.) significantly reduced the heat (P<0.0001) and the mechanical (P=0.0003) withdrawal thresholds, the dose being smaller than that required to reach similar effects in the sciatic nerve constriction model (1.5 mg/kg). When the cannabinoid tetrad test was evaluated to measure behavioral modifications, it was found that WIN 55,212-2 (1mg/kg) did not induce changes either in body temperature or in immobility time, and only a reduction in spontaneous motility was recorded. This effect was antagonized by SR 141716A, suggesting the involvement of the CB1 receptor, although the participation of CB2 receptors cannot be excluded from this study. When WIN 55,212-2 was administered intraplantar, no differences were observed between the injected paw and the contralateral paw, suggesting that systemic mechanisms are needed to reach effectiveness. From these results we suggest that cannabinoids may be an interesting alternative to reduce neuropathic symptoms induced by paclitaxel, however more work is required to assess this possibility.
Pascual
David
D
Unidad Farmacología, Departamento de Ciencias de la Salud III, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. Atenas s/n, Alcorcón, Madrid, 28922, Spain.
Goicoechea
Carlos
C
Suardíaz
Margarita
M
Martín
María Isabel
MI
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D048588:Benzoxazines; D002186:Cannabinoids / Q000819:agonists / Q000494:pharmacology; D004195:Disease Models, Animal; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000175:diagnosis / Q000517:prevention & control; D008297:Male; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D009437:Neuralgia / Q000139:chemically induced* / Q000188:drug therapy* / Q000517:prevention & control; D017239:Paclitaxel / Q000009:adverse effects* / Q000627:therapeutic use / Q000633:toxicity*; D010147:Pain Measurement / Q000379:methods; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000517:prevention & control; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D012684:Sensory Thresholds / Q000187:drug effects / Q000502:physiology; D014110:Touch / Q000502:physiology; D016896:Treatment Outcome
D000700:Analgesics; D000972:Antineoplastic Agents, Phytogenic; D048588:Benzoxazines; D002186:Cannabinoids; 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; D017239:Paclitaxel