Inflammation enhances Y1 receptor signaling, neuropeptide Y-mediated inhibition of hyperalgesia, and substance P release from primary afferent neurons.

Abstract

Neuropeptide Y (NPY) is present in the superficial laminae of the dorsal horn and inhibits spinal nociceptive processing, but the mechanisms underlying its anti-hyperalgesic actions are unclear. We hypothesized that NPY acts at neuropeptide Y1 receptors in the dorsal horn to decrease nociception by inhibiting substance P (SP) release, and that these effects are enhanced by inflammation. To evaluate SP release, we used microdialysis and neurokinin 1 receptor (NK1R) internalization in rat. NPY decreased capsaicin-evoked SP-like immunoreactivity in the microdialysate of the dorsal horn. NPY also decreased non-noxious stimulus (paw brush)-evoked NK1R internalization (as well as mechanical hyperalgesia and mechanical and cold allodynia) after intraplantar injection of carrageenan. Similarly, in rat spinal cord slices with dorsal root attached, [Leu(31), Pro(34)]-NPY inhibited dorsal root stimulus-evoked NK1R internalization. In rat dorsal root ganglion neurons, Y1 receptors colocalized extensively with calcitonin gene-related peptide (CGRP). In dorsal horn neurons, Y1 receptors were extensively expressed and this may have masked the detection of terminal co-localization with CGRP or SP. To determine whether the pain inhibitory actions of Y1 receptors are enhanced by inflammation, we administered [Leu(31), Pro(34)]-NPY after intraplantar injection of complete Freund's adjuvant (CFA) in rat. We found that [Leu(31), Pro(34)]-NPY reduced paw clamp-induced NK1R internalization in CFA rats but not uninjured controls. To determine the contribution of increased Y1 receptor-G protein coupling, we measured [(35)S]GTPγS binding simulated by [Leu(31), Pro(34)]-NPY in mouse dorsal horn. CFA inflammation increased the affinity of Y1 receptor G-protein coupling. We conclude that Y1 receptors contribute to the anti-hyperalgesic effects of NPY by mediating the inhibition of SP release, and that Y1 receptor signaling in the dorsal horn is enhanced during inflammatory nociception.

• Authors: B K Taylor, W Fu, K E Kuphal, C-O Stiller, M K Winter, W Chen, G F Corder, J H Urban, K E McCarson, J C Marvizon
• Journal: Neuroscience (Neuroscience) Vol. 256 Pg. 178-94 (Jan 03 2014) ISSN: 1873-7544 [Electronic] United States
• PMID: 24184981 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Neuropeptide Y
• Receptors, Neurokinin-1
• Receptors, Neuropeptide Y
• Sulfur Isotopes
• Substance P
• Guanosine 5'-O-(3-Thiotriphosphate)
• Freund's Adjuvant

Topics

• Animals
• Freund's Adjuvant (pharmacology)
• Guanosine 5'-O-(3-Thiotriphosphate) (pharmacokinetics)
• Hyperalgesia (etiology, pathology)
• In Vitro Techniques
• Inflammation (chemically induced, complications, pathology)
• Male
• Neurons, Afferent (drug effects, physiology)
• Neuropeptide Y (metabolism)
• Pain Measurement
• Pain Threshold (drug effects)
• Protein Binding (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Neurokinin-1 (metabolism)
• Receptors, Neuropeptide Y (metabolism)
• Signal Transduction (drug effects, physiology)
• Spinal Cord (pathology)
• Spinal Nerve Roots (physiology)
• Substance P (metabolism)
• Sulfur Isotopes (pharmacokinetics)