Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain.
Ziconotide (SNX-111), a selective blocker of neuronal N-type voltage-sensitive calcium channels, is antinociceptive when it is administered intrathecally. It is currently under clinical investigation for the treatment of malignant and non-malignant pain syndromes. The present study was undertaken to compare and contrast antinociceptive properties of ziconotide, morphine and clonidine in a rat model of post-operative pain. Post-operative pain was produced by making a longitudinal incision through the skin, fascia, and muscle of the plantar aspect of the left hindpaw. This procedure produced immediate (0.5 h after surgery) and long-lasting (4-7 days post-surgery) heat hyperalgesia and mechanical allodynia in the injured hindpaw. Pain thresholds in the contralateral hindpaw were unaffected. Administered one day after incisional surgery, intrathecal ziconotide blocked established heat hyperalgesia in the injured hindpaw in a dose-dependent manner yielding an ED(50)4 h) but reversible (<24 h) blockade of established mechanical allodynia. Administered one day after surgery, intrathecal bolus injection of morphine dose-dependently blocked heat hyperalgesia in the injured hindpaw with an ED(50) of 1.6 microg (2.1 nmol) and heat nociceptive responses in the normal hindpaw with an ED(50) of 2.7 microg (3.6 nmol). The effects were immediate and short-lasting (</=1 h). Intravenous bolus injection of 3 mg/kg (1.1 micromol/kg) ziconotide, administered either before or after incisional surgery, had no effect on thermal pain thresholds measured in either the injured or normal hindpaw. In contrast, intraperitoneal injections of 2 mg/kg (2.6 micromol/kg) morphine and 2.5 mg/kg (9.4 micromol/kg) clonidine blocked heat hyperalgesia in the injured hindpaw; morphine, but not clonidine, also elevated thermal (heat) nociceptive response thresholds in the normal hindpaw. The results of this study show that intrathecal ziconotide is antinociceptive in a rat incisional model of post-operative pain and is more potent, longer acting, and more specific in its actions than intrathecal morphine.
Wang
Y X
YX
Department of Pharmacology, Elan Pharmaceuticals, 3760 Haven Avenue, Menlo Park, CA 94025, USA. jwang@elanpharma.com
Pettus
M
M
Gao
D
D
Phillips
C
C
Scott Bowersox
S
S
D000700:Analgesics / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology*; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D010149:Postoperative Pain / Q000503:physiopathology*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020960:omega-Conotoxins / Q000008:administration & dosage / Q000494:pharmacology*
D000700:Analgesics; D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020960:omega-Conotoxins; D009020:Morphine; C078452:ziconotide; D003000:Clonidine