Inhibitory G_i/O-coupled receptors in somatosensory neurons: Potential therapeutic targets for novel analgesics

Primary sensory neurons in the dorsal root ganglia and trigeminal ganglia are responsible for sensing mechanical and thermal stimuli, as well as detecting tissue damage. These neurons express ion channels that respond to thermal, mechanical, or chemical cues, conduct action potentials, and mediate transmitter release. These neurons also express a large number of G-protein coupled receptors, which are major transducers for extracellular signaling molecules, and their activation usually modulates the primary transduction pathways. Receptors that couple to phospholipase C via heterotrimeric G_q/11 proteins and those that activate adenylate cyclase via G_s are considered excitatory; they positively regulate somatosensory transduction and they play roles in inflammatory sensitization and pain, and in some cases also in inducing itch. On the other hand, receptors that couple to G_i/o proteins, such as opioid or GABA_B receptors, are generally inhibitory. Their activation counteracts the effect of G_s-stimulation by inhibiting adenylate cyclase, as well as exerts effects on ion channels, usually resulting in decreased excitability. This review will summarize knowledge on G_i-coupled receptors in sensory neurons, focusing on their roles in ion channel regulation and discuss their potential as targets for analgesic and antipruritic medications.