Phosphodiesterase 10A inhibitors reverse acute and inflammatory pain in mice

Acute and chronic pain, although common, are often poorly treated by existing therapies. Accordingly, there is a substantial unmet medical need for safe and efficacious treatments. Recent studies revealed that cyclic nucleotide phosphodiesterases (PDE) contribute to the processing of pain, and that PDE might be targets for pain therapy. Here we found that the PDE10A isoform is expressed in pain processing neurons in dorsal root ganglia (DRG) and the spinal cord in mice. Incubation of DRG neuron cultures with a selective PDE10A inhibitor increased the cGMP levels in enzyme immunoassays. Real-time FRET-based cGMP imaging confirmed increased cGMP signals in DRG neurons after PDE10A inhibition. Notably, PDE10A inhibitor treatment inhibited the pain behavior in mice in models of acute nociceptive pain and persistent inflammatory pain without the development of antinociceptive tolerance. Together, our data support the idea that PDE10A is a suitable target for development of efficacious analgesic drugs.