Ziconotide is a selective, potent and reversible blocker of neuronal N-type 
voltage-sensitive calcium channels (VSCCs). Morphine is an agonist of mu-opioid 
receptors and inhibits N-type VSCC channels via a G-protein coupling mechanism. 
Both agents are antinociceptive when they are administered intrathecally 
(spinally). The present study investigated the acute and chronic (7-day) 
interactions of intrathecally administered ziconotide and morphine on 
nociception in several animal models of pain. In the acute study, intrathecal 
bolus injections of morphine and ziconotide alone produced dose-dependent 
inhibition of formalin-induced tonic flinch responses and withdrawal responses 
to paw pressure. The combination of ziconotide and morphine produced an additive 
inhibition of formalin-induced tonic flinch responses and a significant leftward 
shift of the morphine dose-response curve in the paw pressure test. After 
chronic (7-day) intrathecal infusion, ziconotide enhanced morphine analgesia in 
the formalin test. In contrast, chronic intrathecal morphine infusion produced 
tolerance to analgesia, but did not affect ziconotide antinociception. 
Antinociception produced by ziconotide alone was the same as that observed when 
the compound was co-administered with morphine to morphine-tolerant rats. In the 
hot-plate and tail immersion tests, chronic intrathecal infusion of morphine 
lead to rapid tolerance whereas ziconotide produced sustained analgesia with no 
loss of potency throughout the infusion period. Although ziconotide in 
combination with morphine produced an apparent synergistic analgesic effects 
during the initial phase of continuous infusion, it did not prevent morphine 
tolerance to analgesia. These results demonstrate that (1) acute intrathecal 
administrations of ziconotide and morphine produce additive or synergistic 
analgesic effects; (2) chronic intrathecal morphine infusion results in 
tolerance to analgesia but does not produce cross-tolerance to ziconotide; (3) 
chronic intrathecal ziconotide administration produces neither tolerance nor 
cross-tolerance to morphine analgesia; (4) intrathecal ziconotide does not 
prevent or reverse morphine tolerance.