The role of Y1R-expressing dorsal horn interneurons in pain

Abstract

The spinal Neuropeptide Y (NPY) system is a potential target for development of new pain therapeutics. NPY and two of its receptors (Y1 and Y2) are found in the superficial dorsal horn of the spinal cord, a key area of nociceptive gating and modulation. Lumbar intrathecal injection of Neuropeptide Y (NPY) is antinociceptive, reducing hyper-reflexia to thermal and mechanical stimulation, particularly after nerve injury and inflammation. We have previously shown that intrathecal injection of the targeted cytotoxin, Neuropeptide Y-sap (NPY-sap), is also antinociceptive, reducing nocifensive reflex responses to noxious heat and formalin. In the present study, we sought to determine the role of dorsal horn Y1R-expressing neurons in pain by destroying them with NPY-sap and testing the rats on three operant tasks. We also sought to determine the extent and selectivity of the lesion by staining tissue from rats injected with other peptide-saporin conjugates, Derm-sap and Gal-sap, for the Y1 receptor, and, conversely, staining the NPY-sap tissue for MOR and Gal-R1. Lumbar intrathecal NPY-sap 1- reduced CFA-induced hyper-reflexia on the 10°C cold plate, 2- reduced cold aversion on the thermal preference and escape tasks, 3- was analgesic to noxious heat on the escape task, 4- reduced the CFA-induced allodynia to cold temperatures experienced on the thermal preference, feeding interference, and escape tasks, 5- did not inhibit or interfere with morphine analgesia, and 6- reduced immunoperoxidase staining for Y1R in the superficial dorsal horn. These data indicate that Y1R-expressing dorsal horn neurons play an important role in pain modulation, particularly after peripheral inflammation. The involvement of Y1R-expressing neurons in modulating cold pain and the observation that intrathecal injection of NPY-sap does not interfere with morphine analgesia, along with our previous findings that intrathecal NPY-sap doesn’t affect protective reflexes, pose Y1R-expressing dorsal horn neurons as excellent candidates to be targeted for the development of analgesic drugs.