The cell bodies of nociceptors are contained within the dorsal root ganglia and terminate as free endings in peripheral tissues. The peripheral terminals respond to noxious stimuli or tissue damage through receptors and ion channels including TRP channels, acid-sensing ion channels (ASIC), serotonin (5-HT) receptors, ATP-gated P2X receptors, tyrosine kinase receptor A (TRKA), and numerous GPCRs that indirectly activate ion channels. Receptors at the terminals respond to noxious stimuli such as heat or pressure (i). When a defined threshold of depolarization is reached, voltage-gated sodium channels are activated and an action potential is generated (ii). During an action potential, an IFM-inactivating segment moves to block the channel within 0.5–1 ms (iii). In this inactivated state, the channel cannot be opened. Meanwhile, potassium channels open, acting to repolarize the membrane. As the membrane repolarizes, the sodium channel gate is closed and inactivating segment is displaced, returning the sodium channel to a resting closed state (iii). This process is repeated to propagate the action potential along the axon (ii). The action potential is propagated along the axon to the presynaptic terminals synapses with second-order neurons in the dorsal horn. Calcium influx through voltage-gated calcium channels (VGCC) triggers the release of neurotransmitters such as glutamate from presynaptic terminals (iv). Glutamate activates ionotropic AMPA, NMDA receptor (NDMAR), and metabotropic glutamate receptors (mGluR) on the postsynaptic terminals in the spinal cord, and the signal is transmitted through the ascending pathways to higher centers in the brain.