title: Analysis of the anti-allodynic effects of combination of a synthetic cannabinoid and a selective noradrenaline re-uptake inhibitor in nerve injury-induced neuropathic mice.
abstract: BACKGROUND
  Combining drugs not only reduces specific adverse effects of each of the drug at a higher dose but also may lead to enhanced efficacy. Tapentadol is a recently discovered analgesic possessing μ-opioid receptor agonism and noradrenaline re-uptake inhibition in a single molecule. Taking into consideration, the pharmacological similarities between opioids and cannabinoids, we assumed that combination of cannabinoids with noradrenaline re-uptake inhibitors might also be effective. We therefore aimed to determine whether combining 1:1, 1:3 and 3:1 fixed ratios of the synthetic cannabinoid WIN 55,212-2 and the selective noradrenaline re-uptake inhibitor maprotiline exert anti-allodynic synergy on nerve-injured neuropathic mice.
  
  
  METHODS
  Partial tight ligation of the sciatic nerve was made in mice; on pre-operative and post-operative 15 days basal mechanical allodynia, cold allodynia and motor function were assessed using von Frey filaments, hot/cold plate and rota rod apparatus.
  
  
  RESULTS
  Mechanical and cold allodynia developed in all groups on post-operative 15 days. Development of cold allodynia was statistically significant in all groups (p < 0.05); therefore, cold allodynia was used in combination studies. As shown by isobolographic analysis, interactions of 1:1 and 3:1 ratios of WIN 55,212-2:maprotiline combinations were supra-additive, whereas 1:3 ratio was sub-additive.
  
  
  CONCLUSIONS
  Overall, our data suggest that combination of a cannabinoid with a selective noradrenaline re-uptake inhibitor may offer a beneficial treatment option for neuropathic pain.
authors.affiliation: Department of Medical Pharmacology, Faculty of Medicine, Trakya University, 22030-Edirne, Turkey.
authors.forename: O
authors.initials: O
authors.lastname: Gunduz
authors.affiliation: Department of Medical Pharmacology, Faculty of Medicine, Trakya University, 22030-Edirne, Turkey.
authors.forename: R D
authors.initials: RD
authors.lastname: Topuz
authors.affiliation: Department of Medical Pharmacology, Faculty of Medicine, Trakya University, 22030-Edirne, Turkey.
authors.forename: C H
authors.initials: CH
authors.lastname: Karadag
authors.affiliation: Department of Medical Pharmacology, Faculty of Medicine, Trakya University, 22030-Edirne, Turkey.
authors.forename: A
authors.initials: A
authors.lastname: Ulugol
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000818:Animals; D048588:Benzoxazines / Q000627:therapeutic use*; D002186:Cannabinoids / Q000627:therapeutic use*; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D008026:Ligation; D008297:Male; D008376:Maprotiline / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000627:therapeutic use*; D009437:Neuralgia / Q000188:drug therapy*; D010812:Physical Stimulation; D012584:Sciatic Nerve / Q000293:injuries
chemical_list: D018759:Adrenergic Uptake Inhibitors; D048588:Benzoxazines; D002186:Cannabinoids; D004338:Drug Combinations; D009025:Morpholines; D009281:Naphthalenes; D008376:Maprotiline; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone