Background

Neuropeptide Y (NPY) Y2 receptor (Y2) antagonist BIIE0246 can both inhibit and facilitate nociception. The authors hypothesized that Y2 function depends on inflammation or nerve injury status.

Methods

The authors 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 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 guanosine-5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding assays.

Results

The authors 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 pharmacologic 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 peptide YY (3-36) (PYY3-36), but increased the population of Y2 that effectively coupled G-proteins. Intrathecal PYY3-36 failed to reduce spared nerve injury- or incision-induced hypersensitivity in C57BL/6N mice. Incision did not change Npy2r gene expression in dorsal root ganglion.

Conclusions

The authors conclude that Y2 at central terminals of primary afferent neurons provides 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 couples to G-proteins. These results support the development of Y2 antagonists for the treatment of chronic postsurgical and neuropathic pain.

Editor’s Perspective
What We Already Know about This Topic
  • Neuropeptide Y, acting through its G-protein–coupled receptor, Y1, plays a central role in nociception and itch
  • Central terminals of primary afferent neurons densely express the Y2 receptors, but the context-dependent role of these receptors in mediating nociception and itch is incompletely understood
What This Article Tells Us That Is New
  • Pharmacologic antagonism of Y2 receptors increased nociception and itch in uninjured mice, and these effects were mitigated by sensory neuron–specific deletion of Y2 receptors
  • In contrast, both pharmacologic blockade and conditional deletion of Y2 reduced nociception in experimental mouse models of surgical and neuropathic pain
  • These results suggest that Y2 receptors at central terminals of primary afferent neurons provide tonic inhibition to nociception and itch under normal conditions but promote hyperalgesia in persistent pain states