Potassium channels and pain: present realities and future opportunities

Four families of potassium channels with different structures, functional characteristics and pharmacological sensitivity, are distinguished in neurons: voltage-gated (K(v)), calcium-activated (K(Ca)), inward rectifier (K(ir)) and two-pore (K(2P)) K(+) channels. During the last 15 years, numerous studies have demonstrated that the opening of some of these K(+) channels plays an important role in the antinociception induced by agonists of many G-protein-coupled receptors (alpha(2)-adrenoceptors, opioid, GABA(B), muscarinic M(2), adenosine A(1), serotonin 5-HT(1A) and cannabinoid receptors), as well as by other antinociceptive drugs (nonsteroidal antiinflammatory drugs [NSAIDs], tricyclic antidepressants, etc.) and natural products. Several specific types of K(+) channels are involved in antinociception. The most widely studied are the ATP-sensitive K(+) channels (K(ATP)), members of the K(ir) family, which participate in the antinociception induced by many drugs that activate them in both the central and the peripheral nervous system. The opening of G-protein-regulated inwardly rectifying K(+) channels (GIRK or K(ir)3), K(v)1.1 and two types of K(Ca) channels, the small- and large-conductance calcium-activated K(+) channels (SK and BK channels, respectively), also play a role in the antinociceptive effect of different drugs and natural products. Recently, drugs that open K(+) channels by direct activation (such as openers of neuronal K(v)7 and K(ATP) channels) have been shown to produce antinociception in models of acute and chronic pain, which suggests that other neuronal K(+) channels (e.g. K(v)1.4 channels) may represent an interesting target for the development of new K(+) channel openers with antinociceptive effects.