Calcium Channels and Pain Part V. (ziconotide) J. McGivern and S. McDonough

This is a further review of material provided to painonline by McGivern and McDonough. We thank them deeply for their input. For what it is worth, they are experts on sodium channels as well, but we review only their publications on calcium channels. And once again, we are glad a company such as Amgen has this caliber of researchers on board.

Knockout mice are genetically altered mice where a given gene has been deleted to study the effects of that gene. This is the method usually followed to learn what function a given gene performs, ie. what protein it manufactures, and what that protein does.

Currently, there are three different strains of CaV2.2 knockout mice. Most significantly, these mice seem to be free of neurological defects and are apparently otherwise healthy. The other calcium currents do not upregulate to compensate for the loss of CaV2.2 in the neurons studied so far, in the superior cervical ganglia (sympathetic autonomic nervous system) and in the dorsal root ganglia (where sensory neurons have their cell bodies receiving messages from the peripherae and then being fed into the cord. (the dorsal root ganglia is just outside the cord).

When formalin is injected, (chemical pain) there is some reduction in flinching when the irritated paw is touched. However, in the spinal nerve ligation model of neuropathic pain, CaV2.2 knockout mice display markedly reduced allodynia from BOTH thermal and mechanical (touch) stimulus. No models of central pain in these knockout rats have yet been tested. However, the peripheral nerve injury models typically transfer and apply to central pain as well. These models have been confirmed on the cellular level by injecting formalin and then noting that sensitized cells in the dorsal horn of the cord are more likely to be silenced by the omega conotoxins. This corresponds to the dorsal horn neurons in models of neuropathic pain as well, when induced by injury to the sciatic nerve (supplies the back of the thigh and into leg). The omegao conotoxin MVIIA treats the neuropathic pain of ligation AND all conotoxins tested prevent pain from formalin injection AND eliminate heat hyperalgesia produced by injection of carrageenan. Although not all conotoxins have been tested, the results should be similar between GVIA, MVIIA, and CVID The similar peptide, agatoxin, helps inflammatory pain but does NOT treat neuropathic pain. What is really odd is that agatoxin DOES inhibit the calcium channels in spinal cord and dorsal root ganglia, so there is another step involved in neuropathic pain which needs to be understood. For unknown reasons, CaV2.2 channels dominate the calcium currents which release pain neurotransmitters.

Ziconotide (Prialt) is currently the only conotoxin in real use. It is given into the fluid around the spinal cord (intrathecally) to avoid effects on the sympathetic neurons and slowing of the heart. Ziconotide is synthetic form of MVIIA, copied from the toxin of the shellfish, Conus magus. It blocks N type channels, among others, and also inhibits windup in the central nervous system, which is a type of central sensitization. Although reports are almost all from safety studies, where dosages are pushed and questioning is particular, 30% of users report side effects from ziconotide, such as confusion, dizziness, and nausea. Because the worst side effects occur at high doses, above the concentrations needed to block CaV2.2, it is felt that the side effects may be due to off target effects on other calcium channels or via effects on P2X receptors. (For more information on P2X receptors, use SEARCH at this site). Currently it is used only for terminal cancer patients and a few with severe neuropathic pain. It is also costly. The search from here will be for agents which block only the N type channel in hyperexcitable neurons, and can be taken orally.