Major neurotransmitters involved in antinociceptive functions
Dorsal horn nociception can be regulated by both local inhibitory interneurons and descending inhibitory pathways that arise in the brainstem. The majority of inhibitory interneurons use the neurotransmitters, gamma-aminobutyric acid (GABA) or glycine. These neurotransmitters inhibit the firing of dorsal horn nociceptive neurons by both presynaptic and postsynaptic controls. Other interneurons contain one of the endorphin peptides: enkephalin or dynorphin. These increase potassium conductance, thereby hyperpolarizing neurons. In some cases, they presynaptically block the release of neurotransmitters from primary afferent fibers by decreasing calcium conductance. The major descending inhibitory pathways use either serotonin or norepinephrine. Consistent with the presence of these diverse inhibitory neurotransmitter mechanisms, intrathecal injection of a variety of compounds (e.g., opioids, clonidine) produces profound antinociceptive effects.
Another major approach to regulating nociceptive processing is to influence Ca 2+ channel function on primary afferents. Reduction of voltage-gated Ca 2+ channels will result in decreased transmitter release. This can be generated directly, via drugs that act on the channel. For example, gabapentin binds to the αδ2 subunit of a variety of Ca 2+ channels. Ziconotide, a cone snail–derived peptide approved for intrathecal use in the treatment of pain in patients who already carry an intrathecal pump, blocks the N-type calcium channel. Morphine and other opioids reduce Ca 2+ channel activity as well as increase K channel activity, producing presynaptic and postsynaptic inhibition, respectively of dorsal horn “pain” transmission neurons.