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Pathway Description
Ziconotide Analgesia Action Pathway
Homo sapiens
Drug Action Pathway
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.
References
Ziconotide Analgesia Pathway References
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Park J, Luo ZD: Calcium channel functions in pain processing. Channels (Austin). 2010 Nov-Dec;4(6):510-7. doi: 10.4161/chan.4.6.12869. Epub 2010 Nov 1.
Pubmed: 21150297
Simms BA, Zamponi GW: Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron. 2014 Apr 2;82(1):24-45. doi: 10.1016/j.neuron.2014.03.016.
Pubmed: 24698266
Bourinet E, Altier C, Hildebrand ME, Trang T, Salter MW, Zamponi GW: Calcium-permeable ion channels in pain signaling. Physiol Rev. 2014 Jan;94(1):81-140. doi: 10.1152/physrev.00023.2013.
Pubmed: 24382884
Evans AR, Nicol GD, Vasko MR: Differential regulation of evoked peptide release by voltage-sensitive calcium channels in rat sensory neurons. Brain Res. 1996 Mar 18;712(2):265-73. doi: 10.1016/0006-8993(95)01447-0.
Pubmed: 8814901
Maggi CA, Tramontana M, Cecconi R, Santicioli P: Neurochemical evidence for the involvement of N-type calcium channels in transmitter secretion from peripheral endings of sensory nerves in guinea pigs. Neurosci Lett. 1990 Jul 3;114(2):203-6. doi: 10.1016/0304-3940(90)90072-h.
Pubmed: 1697665
Smith MT, Cabot PJ, Ross FB, Robertson AD, Lewis RJ: The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. Pain. 2002 Mar;96(1-2):119-27. doi: 10.1016/s0304-3959(01)00436-5.
Pubmed: 11932068
Bourinet E, Zamponi GW: Block of voltage-gated calcium channels by peptide toxins. Neuropharmacology. 2017 Dec;127:109-115. doi: 10.1016/j.neuropharm.2016.10.016. Epub 2016 Oct 15.
Pubmed: 27756538
Russell FA, King R, Smillie SJ, Kodji X, Brain SD: Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014 Oct;94(4):1099-142. doi: 10.1152/physrev.00034.2013.
Pubmed: 25287861
Zhang Y, Lin C, Wang X, Ji T: Calcitonin gene-related peptide: A promising bridge between cancer development and cancer-associated pain in oral squamous cell carcinoma. Oncol Lett. 2020 Nov;20(5):253. doi: 10.3892/ol.2020.12116. Epub 2020 Sep 18.
Pubmed: 32994816
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