Ziconotide 500micrograms/5ml solution for infusion vials

Nociceptive pain signalling is a complex processing pathway involving peripheral nociceptors, primary afferent nerve fibres, and downstream CNS neurons located in the spinal cord.[A202838][A202859] Voltage-gated calcium channels (VGCCs) are important regulatory components of neural signalling and include the N-type (Cav2.2) heteromultimeric high-voltage type calcium channels.[A202844] Chronic pain conditions, including inflammatory and neuropathic pain, often involve the aberrant upregulation of VGCC activity through various cellular mechanisms, which can lead to allodynia and hyperalgesia.[A202859]

Specifically, N-type channel activation in lightly myelinated Aδ- and C-fibres is known to mediate the release of neurotransmitters substance P (SP), calcitonin gene-related peptide (CGRP), and glutamate, which influence downstream neural activation and pain perception.[A202838][A202859][A202868][A202871][A202874] In addition, SP and CGRP induce inflammation, potentially exacerbating pre-existing inflammatory chronic pain.[A202859]

Ziconotide belongs to the ω-conotoxin class of neurotoxic peptides derived from the cone snail Conus magus which are capable of inhibiting N-type VGCCs.[A202826][A202829][A202835][A202841][L13389] Although the exact mechanism is yet to be elucidated, it is thought that ω-conotoxins function through direct occlusion of the ion pore to prevent calcium translocation across the membrane.[A202841] Additional studies involving expression of chimeric subunits and molecular modelling suggest that insertion of the ziconotide Met¹² residue into a hydrophobic pocket formed by Ile³⁰⁰, Phe³⁰², and Leu³⁰⁵ of Cav2.2 increases binding and may be associated with toxic adverse effects.[A202847]