Pain pathways and their regulation through WT and VT signals integrated through receptor-receptor interactions in heteromers. (left) A schematic overview of the ascending main circuits mediating pain. When a noxious stimulus is encountered. Afferent nociceptors convey noxious information to projection neurons within the dorsal horn of the spinal cord. Neurotransmitters released here bind to and activate postsynaptic receptors on pain transmission neurons. In turn, the axons of pain transmission neurons ascend, predominantly contralaterally, to the brain and carry the information about the noxious stimulus to higher centers (somatosensory cortex via the thalamus with information about location and intensity of the painful stimulus or the insular cortices via connections in the brainstem (parabranchial nucleus) and amygdala within the affective component of the pain experience). The descending inhibitory pathways to the dorsal horn from the brainstem involving interalia the NA, 5HT, and DA pathways (see text) are also indicated. They exert antinociceptive actions in the pain circuits of the dorsal horn. (right) The diagram shows a few prominent of many possible mediators and cell-cell interactions in the spinal cord dorsal horn, thalamus, or amygdala. In these pain circuits opioid receptor containing heteromers may play a role in the modulation of pain transmission, offering novel targets for antinociceptive drugs. The enkephalin peptides (short distance diffusion) and b-endorphin (long distance diffusion) mainly operate via VT and likely modulate the pain circuits via receptor-receptor interactions in receptor heteromers built-up of synaptic protomers and of opioid receptor protomers. In this way synaptic transmission signals and VT signals become integrated giving a balance in nociceptive and antinociceptive signaling in the CNS. The descending inhibitory pathways to the dorsal horn involving inter alia the monoamine pathways also mainly communicate via VT (see text).