CNSB004 (Leconotide) causes antihyperalgesia without side effects when given intravenously: a comparison with ziconotide in a rat model of diabetic neuropathic pain.
OBJECTIVE
Leconotide is an omega-conotoxin that blocks neuronal voltage sensitive calcium channels. This study compared the antihyperalgesic potencies of leconotide and ziconotide given intravenously alone and in combinations with a potassium channel modulator flupirtine, given intraperitoneally, in a rat model of diabetic neuropathic pain.


METHODS
Rats were given streptozotocin (150 mg/kg ip) to induce diabetic neuropathy and hyperalgesia. Experiments were performed on diabetic rats with >or=30% hyperalgesia to noxious heat. Rats were given each conopeptide alone and with flupirtine. Open field activity monitoring and non-invasive blood pressure measurements were used to define the maximum doses and combinations that caused no side effects. Doses in a range up to maximum no side effect doses were tested for antihyperalgesic effects in rats with hyperalgesia.


RESULTS
The maximum no side effect dose of leconotide (2 mg/kg intravenously) caused 51.7% reversal of hyperalgesia compared with 0.4% for the highest no side effect dose of ziconotide (0.02 mg/kg; P < 0.001, one-way anova). Leconotide caused dose-related antihyperalgesic effects that were potentiated by coadministration with flupirtine at doses that were ineffective when given alone. Leconotide (0.02 mg/kg) and flupirtine (5 mg/kg) caused 25.3 +/- 7.6 and -6 +/- 9.5% reversal of hyperalgesia, respectively when given alone but in combination they caused 84.1 +/- 7.2% reversal of hyperalgesia (P < 0.01; one-way anova). No such interaction occurred with ziconotide.


CONCLUSIONS
Leconotide could have wider clinical applications than ziconotide. Unlike ziconotide, powerful antihyperalgesia without side effects can be achieved by intravenous administration of leconotide thus avoiding the need for an intrathecal injection.
Kolosov
Anton
A
Centre for Pain Medicine and Palliative Care, Monash Institute of Medical Research, Monash University, Clayton, Victoria. anton.kolosov@med.monash.edu.au
Goodchild
Colin S
CS
Cooke
Ian
I
D000631:Aminopyridines / Q000627:therapeutic use; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003929:Diabetic Neuropathies / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006439:Hemodynamics / Q000187:drug effects; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D007275:Injections, Intravenous; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020960:omega-Conotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
C461486:AM336; D000631:Aminopyridines; D018712:Analgesics, Non-Narcotic; D002121:Calcium Channel Blockers; D020960:omega-Conotoxins; C078452:ziconotide; C034161:flupirtine