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 doesnt affect protective reflexes, pose Y1R-expressing dorsal horn neurons as excellent candidates to be targeted for the development of analgesic drugs.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11302011-094038 |
| Date | 20 December 2011 |
| Creators | Lemons, Laurie Lee |
| Contributors | Sukhbir Mokha, Li Min Chen, Craig Kennedy, Ronald WIley |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu//available/etd-11302011-094038/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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