Ziconotide, also known as SNX-111, is an N-type calcium channel antagonist used to manage patients with severe chronic pain who cannot tolerate, or who have not responded adequately to other treatments such as intrathecal morphine and systemic analgesics. Ziconotide is a neurotoxic peptide derived from the cone snail Conus magus comprising 25 amino acids with three disulphide bonds. It is used to manage severe chronic pain through the inhibition of N-type calcium channels involved in nociceptive signalling.Ziconotide was granted FDA approval on December 28, 2004 under the brand name Prialt. To date, ziconotide is the only calcium channel blocking peptide approved for use by the FDA. Nociceptive pain signalling is a complex processing pathway involving peripheral nociceptors, primary afferent nerve fibres, and downstream CNS neurons located in the spinal cord such as the dorsal root ganglion. Voltage-gated calcium channels (VGCCs) are important regulatory components of neural signalling, including type-N voltage-gated calcium channels. N-type channel activate lightly myelinated Aδ- and C-fibres, which mediate the release of neurotransmitters substance P, calcitonin gene-related peptide (CGRP), and glutamate. This causes downstream nociceptive neuronal activity and pain perception. Substance P and CGRP both also induce inflammation, further exasperating chronic pain. Ziconotide inhibits Voltage-dependent N-type calcium channels in presynaptic neurons. This prevents calcium from entering the neuron which prevents neurotransmitter release from the dorsal root ganglion as well as other nociceptive neurons. Therefore substance P, CGRP, and glutamate are not released into the synapse and cannot activate the substance P receptors, CGRP receptors, or the N-Methyl-D-aspartic acid receptors on the post-synaptic neuron. This causes hyperpolarization, with a down-stream effect of hyperalgesia, a prevention of pain signalling.

Ziconotide NMDA and Substance P Receptor Pain Inhibition Pathway References