Voltage-gated calcium channels as molecular targets for pain therapeutics

抄録

Voltage-gated calcium channels are important for the transmission of pain signals. N-type calcium channels are expressed in the synaptic terminals of primary afferent fibers where they control the release of neurotransmitters such as substance P and CGRP. Consequently, inhibiting N-type calcium channels mediates analgesia. In this regard, activation of opioid receptors mediates a G-protein dependent inhibition of N-type calcium channels, thus increasing pain thresholds. N-type calcium channels can also be directly targeted pharmacologically via peptide toxins such as Prialt which physically prevent calcium permeation. Finally, they are regulated by gabapentinoids that interact with the ancillary calcium channel alpha2-delta subunit and reduce the trafficking of the channels to the synapse. On the other hand, upregulation of alpha2-delta expression following nerve injury increases N-type calcium channel density and thus contributes to neuropathic pain. In this context, I will present new data that concern cellular mechanisms that regulate alpha2-delta subunit function and how this can potentially be exploited for the development of new analgesics. I will also present findings concerning opioid receptor regulation of N-type channels and its relevance for morphine tolerance.