title: Intravenous injection of leconotide, an omega conotoxin: synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain.
abstract: OBJECTIVE
  Leconotide (CVID, AM336, CNSB004) is an omega conopeptide similar to ziconotide, which blocks voltage sensitive calcium channels. However, unlike ziconotide, which must be administered intrathecally, leconotide can be given intravenously because it is less toxic. This study investigated the antihyperalgesic potency of leconotide given intravenously alone and in combinations with morphine-administered intraperitoneally, in a rat model of bone cancer pain.
  
  
  METHODS
  Syngeneic rat prostate cancer cells AT3B-1 were injected into one tibia of male Wistar rats. The tumor expanded within the bone causing hyperalgesia to heat applied to the ipsilateral hind paw. Measurements were made of the maximum dose (MD) of morphine and leconotide given alone and in combinations that caused no effect in an open-field activity monitor, rotarod, and blood pressure and heart rate measurements. Paw withdrawal thresholds from noxious heat were measured. Dose response curves for morphine (0.312-5.0 mg/kg intraperitoneal) and leconotide (0.002-200 µg/kg intravenous) given alone were plotted and responses compared with those caused by morphine and leconotide in combinations.
  
  
  RESULTS
  Leconotide caused minimal antihyperalgesic effects when administered alone. Morphine given alone intraperitoneally caused dose-related antihyperalgesic effects (ED(50) = 2.40 ± 1.24 mg/kg), which were increased by coadministration of leconotide 20 µg/kg (morphine ED(50) = 0.16 ± 1.30 mg/kg); 0.2 µg/kg (morphine ED(50) = 0.39 ± 1.27 mg/kg); and 0.02 µg/kg (morphine ED(50) = 1.24 ± 1.30 mg/kg).
  
  
  CONCLUSIONS
  Leconotide caused a significant increase in reversal by morphine of the bone cancer-induced hyperalgesia without increasing the side effect profile of either drug.
  
  
  CONCLUSIONS
  Translation into clinical practice of the method of analgesia described here will improve the quantity and quality of analgesia in patients with bone metastases. The use of an ordinary parenteral route for administration of the calcium channel blocker (leconotide) at low dose opens up the technique to large numbers of patients who could not have an intrathecal catheter for drug administration. Furthermore, the potentiating synergistic effect with morphine on hyperalgesia without increased side effects will lead to greater analgesia with improved quality of life.
authors.affiliation: Laboratory for Pain Medicine and Palliative Care, Monash Institute of Medical Research Centre for Cancer Research, Monash University, Clayton, Victoria, Australia. anton.kolosov@monash.edu
authors.forename: Anton
authors.initials: A
authors.lastname: Kolosov
authors.forename: Lucia
authors.initials: L
authors.lastname: Aurini
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Williams
authors.forename: Ian
authors.initials: I
authors.lastname: Cooke
authors.forename: Colin S
authors.initials: CS
authors.lastname: Goodchild
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal; D001859:Bone Neoplasms / Q000150:complications* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D007275:Injections, Intravenous; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D009483:Neuropsychological Tests; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D013977:Tibia / Q000473:pathology; D014407:Tumor Cells, Cultured; D020960:omega-Conotoxins / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: C461486:AM336; D000700:Analgesics; D020960:omega-Conotoxins; D009020:Morphine