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. Studies have demonstrated that the opening of some of these K⁺ channels plays an important role in the anti-nociception induced by agonists of many G-protein coupled receptors, as well as by other anti-nociceptive drugs and natural products.

Agonists of µ- and δ-opioid receptors open inward rectifier K⁺ channels in neurons through the activation of G_i/o proteins indicating that potassium currents are involved in opioid induced anti-nociception. These currents are involved in both supraspinal and spinal pain relief. In addition, potassium currents are involved in local anti-nociception mediated by peripheral μ-opioid receptors. Local administration of potassium channel antagonists in animal models antagonizes the effect of morphine further ascertaining the involvement of potassium channels in anti-nociception.

NSAID’s anti-nociceptive effect is also partly mediated by potassium currents in the primary afferent nerve endings. Blockers of K_ATP channels, such as sulfonylurea, negate pain relief caused by ketorolac and diclofenac while K_ATP channel openers pinacidil and diazoxide also produce dose-dependent anti-nociception, blocked by sulfonylureas. Opening of the K_V and K_Ca channels does not seem to be involved in NSAID’s anti-nociception in most cases.

Interestingly, cannabinoid receptors are currently not known to be involved in potassium mediated anti-nociception. Anti-nociception induced by cannabinoid receptor agonists is not antagonized by K⁺ channel blockers such as glibenclamide or charybdotoxin suggesting that K_ATP and K_V channels do not play a role in the supraspinal and spinal anti-nociception mediated by cannabinoid receptors¹.