Neuropeptide Y Y2 Receptors in Sensory Neurons Tonically Suppress Nociception and Itch but Facilitate Postsurgical and Neuropathic Pain Hypersensitivity.

ABSTRACT

BACKGROUND: Neuropeptide Y (NPY) Y2 receptor (Y2) antagonist BIIE0246 can both inhibit and facilitate nociception. We hypothesized that Y2 function depends on inflammation or nerve injury status. METHODS: We implemented a battery of behavioral tests in mice of both sexes that received 1) no injury; 2) an incision model of postoperative pain; 3) a spared nerve injury (SNI) model of neuropathic pain; and 4) a latent sensitization model of chronic postsurgical pain. In addition to Y2 gene expression assays, spinal Y2 G-protein coupling was studied with [ 35S]GTPγS binding assays. RESULTS: We report that intrathecal BIIE0246 increased mechanical and cold hypersensitivity, produced behavioral signs of spontaneous nociception and itch, and produced conditioned place aversion and preference in normal, uninjured mice. BIIE0246 did not change heat hypersensitivity or motor coordination. Conditional (sensory neuron-specific) Y2 deletion prevented BIIE0246-induced mechanical and cold hypersensitivity, nocifensive behaviors and aversion. Both conditional deletion and pharmacological blockade of Y2 reduced mechanical and thermal hypersensitivity after incision or nerve injury. SNI did not change the sensitivity of Y2 G-protein coupling with the Y2 agonist PYY3-36, but increased the population of Y2 that effectively coupled G-proteins. Intrathecal PYY3-36 failed to reduce SNI- or incision-induced hypersensitivity in C57BL/6N mice. Incision did not change Npy2r gene expression in dorsal root ganglion. CONCLUSIONS: We conclude that Y2 at central terminals of primary afferent neurons provide tonic inhibition of mechanical and cold nociception and itch. This switches to the promotion of mechanical and thermal hyperalgesia in models of acute and chronic postsurgical and neuropathic pain, perhaps due to an increase in the population of Y2 that effectively couple to G-proteins. These results support the development of Y2 antagonists for the treatment of chronic postsurgical and neuropathic pain.