Figure 2.

Opioid modulation of signaling and synaptic transmission. (a) Presynaptic and postsynaptic effects of opioids on nociception. (Left) Noxious stimuli trigger action potential firing along DRG nociceptors. Upon reaching the synaptic terminal, VGCCs (yellow) open, facilitating neurotransmitter release. These neurotransmitters (e.g., glutamate) then open postsynaptic AMPA and NMDA receptors, which continue the nociceptive signals along pain circuits. (Right) Activation of opioid receptors promotes dissociation of inhibitory G_α and G_βγ protein subunits. G_α subunits suppress adenylate cyclase, and G_βγ subunits presynaptically inhibit VGCC opening and postsynaptically activate GIRK channels, resulting in reduced neurotransmitter release and membrane hyperpolarization, respectively. (b) Biased signaling pathways. Agonist binding to opioid receptors causes conformational changes that promote distinct recruitment of G protein and arrestin effector signaling cascades. While G proteins mediate the inhibitory action of opioid signaling on neurotransmission, arrestin signaling is required both for internalization of opioid receptors and for kinase activities. The balance between G protein and arrestin signaling is thought, in part, to determine the analgesic versus detrimental effects of opioids. (c) Within pain circuits opioid receptors are activated by opioid analgesics such as enkephalin (endogenous) or morphine (exogenous). Endogenous opioids, such as enkephalins, can be released from infiltrating immune cells at the site of injuries and from neurons in the central nervous system. Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; DRG, dorsal root ganglion; EPSC, excitatory postsynaptic current; ERK, extracellular signal regulated kinase; GIRK, G protein gated inwardly rectifying potassium; JNK, c-Jun N-terminal kinase; NMDA, N-methyl-D-aspartate; RVM, rostral ventromedial medulla; VGCC, voltage-gated calcium channel.