A-kinase anchoring protein complexes and cAMP signaling within the dorsal root ganglia in chronic pain.

cAMP signaling is a central regulator of dorsal root ganglion neuron excitability, with spatial and functional specificity conferred by A-kinase anchoring proteins (AKAPs). Here, we examine how cAMP signaling and AKAP-associated signalosomes control nociceptor sensitization and contribute to persistent pain states. We emphasize differential roles of adenylyl cyclase isoforms in dorsal root ganglion neurons and their regulation within AKAP79/150 complexes that coordinate protein kinases, ion channels, and phosphatases to modulate excitability and synaptic plasticity. In pathological conditions such as spinal cord injury, these networks promote sustained hyperexcitability and diminished opioid potency. In particular, AKAP79/150-associated L-type voltage-gated calcium channels are central to circuits involving local calcium influx, extracellular signal-regulated kinase activation, and cAMP signaling that reduce sensitivity to inhibitory Gαi and thus opioids in pathological pain states. These insights identify AKAP-centered signaling hubs as critical integrators of nociceptor function and mechanistically link altered cAMP compartmentation to reduced analgesic efficacy. Targeting these complexes, including modulation of calcium channel activity, represents a promising strategy to restore opioid sensitivity and improve treatment of chronic pain. SIGNIFICANCE STATEMENT: Chronic neuropathic pain remains difficult to treat and is often refractory to standard therapies. This review highlights a critical need to define the molecular mechanisms that sustain nociceptor hyperexcitability. A-kinase anchoring protein-organized signaling complexes in sensory ganglia spatially coordinate adenylyl cyclase, calcium channels, and downstream effectors to drive persistent excitability and reduced opioid sensitivity. Thus, these signalosomes represent promising targets for more effective pain therapeutics.