A representation of the central spinal and peripheral changes that accompany neuropathy. A representation of the central spinal and peripheral changes that accompany neuropathy. The existence of a lesion or disease of a peripheral sensory nerve alters the conduction and transmission of sensory messages. The normal transfer of modalities (top right) onto spinal nociceptive specific (NS) and wide-dynamic range (WDR) neurons is changed by ectopic activity, sensory loss, and changes in ion channels. Spinal cord neurons are subject to many receptor-mediated events, but increases in Ca channel function lead to increased transmitter release so that glutamate causes an enhanced activation of AMPA and NMDA receptors. Substance P acts on neurokinin 1 (NK1) receptors to add to the excitation. Reduced spinal inhibition through γ-aminobutyric acid (GABA) and the transporter potassium-chloride transporter member 5 (KCC2) aids enhanced pain messages. Reduced noradrenaline (NA) descending inhibition via α-2 adrenoceptors and increased 5-hydroxytryptamine (5HT) descending excitation via 5HT3 receptors add to the dominance of excitatory transmission. μ-Opioid receptors (MOR) are found on this circuitry. Solomon Tesfaye et al. Dia Care 2013;36:2456-2465 ©2013 by American Diabetes Association