Calcium influx is believed to play a critical role in the cascade of biochemical events leading to neuronal cell death in a variety of pathological settings, including cerebral ischemia. The synthetic t-conotoxin peptide , which selectively blocks depolarization-induced calcium fluxes through neuronal N-type voltage-sensitive calcium channels, protected the pyramidal neurons in the CAl subfield of the hippocampus from damage caused by transient forebrain ischemia in the rat model of four-vessel occlusion. SNX-111 provided neuroprotection when a single bolus inj,ection was administered intravenously up to 24 hr after the ischemic insult. These results suggest that the window of opportunity for therapeutic intervention after cerebral ischemia may be much longer than previously thought and point to the potential use of t-conopeptides and their derivatives in the prevention or reduction of neuronal damage resulting from ischemic episodes due to cardiac arrest, head trauma, or stroke. Microdialysis studies showed that SNX-1ll was 3 orders of magnitude less potent in blocking potassium-induced glutamate release in the hippocampus than the conopeptide SNX-230, which, in contrast to SNX-11l, failed to show any efficacy in the four-vessel occlusion model of ischemia. These results imply that the ability of a conopeptide to block excitatory amino acid release does not correlate with its neuroprotective efficacy.Transient global ischemia of the forebrain, experimentally induced in rats by occlusion of the four major blood vessels supplying the brain, results in degeneration of a majority of the pyramidal neurons in the CAl region of the hippocampus (1). Neuronal damage following global forebrain ischemia has been attributed to increases in extracellular concentration of excitatory neurotransmitters such as glutamate and the resultant influx of calcium into neurons, which initiates a cascade of calcium-dependent intracellular degradative processes (2-4). However, selective antagonists of excitatory amino acid receptors-in particular, N-methyl-D-aspartate (NMDA) antagonists-have not been effective in protecting the vulnerable CAl neurons in the four-vessel occlusion model of transient forebrain ischemia in rats (5-7). Similarly, classical calcium channel antagonists such as the dihydropyridines, which block L-type calcium channels, have also failed to protect neurons from the consequences of ischemia when administered after the ischemic episode (8, 9). To develop therapies for preventing the brain damage caused by ischemia, we have investigated the utility of selectively blocking N-type calcium channels.Numerous studies suggest that the N-type calcium channels at presynaptic nerve terminals mediate a substantial portion of the calcium-dependent transmitter release in the The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.brain (10-12). The N-type channel has bee...

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.

SNX-111, administered intrathecally by continuous, constant-rate infusion, produced dose-dependent pain relief in a 43-year-old male patient with a 23-year history of intractable deafferentation and phantom limb pain secondary to brachial plexus avulsion and subsequent amputation. Dizziness, blurred vision, and lateral-gaze nystagmus were dose-dependent side effects that resolved with decreasing dose levels. Complete pain relief was achieved in this patient without side effects after dose adjustment. We conclude that SNX-111 is a potent analgesic, antihyperesthesic, and antiallodynic agent. Controlled studies of SNX-111 in patients with malignant and nonmalignant pain syndromes are warranted and are under way.

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 (

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