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The Journal of Neuroscience, April 1, 2002, 22(7):2660-2668

Metabotropic Glutamate Receptor 5 Upregulation in A-Fibers after Spinal Nerve Injury: 2-Methyl-6-(Phenylethynyl)-Pyridine (MPEP) Reverses the Induced Thermal Hyperalgesia

Lindsey J. Hudson³, Stuart Bevan¹, Kara McNair¹, Clive Gentry¹, Alyson Fox¹, Rainer Kuhn², and Janet Winter¹

¹ Novartis Institute for Medical Sciences, London, WC1E 6BS, United Kingdom, ² Novartis Pharma AG, Werk Klybeck, CH-4057 Basel, Switzerland, and ³ Oxford GlycoSciences Ltd., Abingdon, OX14 4RY, United Kingdom

Metabotropic glutamate receptor 5 (mGluR5) protein increased after sciatic nerve section in ipsilateral L4 and L5 DRG neuronal profiles, with most of the increase occurring in myelinated A-fiber somata. mGluR5 also increased in lamina II of the ipsilateral spinal cord and the proximal sciatic nerve stump in this model. After L5 spinal nerve ligation, mGluR5 immunoreactivity increased dramatically not only in damaged L5 but also in the neighboring undamaged L4. Interestingly, after partial sciatic nerve section, mGluR5 expression did not change in either L4 or L5 DRG neuronal profiles.

Both spinal nerve ligation and sciatic nerve partial section produced significant mechanical and thermal hyperalgesia and tactile allodynia. After partial sciatic nerve section, the mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) had no effect on any of these behaviors. However, after L5 spinal nerve ligation, although MPEP failed to alter the induced tactile allodynia or mechanical hyperalgesia, it dose dependently reversed the developed thermal hyperalgesia.

Therefore, reversal of thermal hyperalgesia by MPEP correlates with increased mGluR5 in lumbar DRG A-fiber somata after nerve injury. Furthermore, A-fibers in the uninjured L4 DRG after L5 spinal nerve ligation that have increased mGluR5 are the same A-fibers that newly express vanilloid receptor 1 after such injury. Together, these results suggest that, after L5 spinal nerve injury, mGluR5 expression on A-fibers is essential to the development of thermal hyperalgesia. After partial nerve section, however, it is unlikely that thermal responses are mediated through mGluR5 because no such increase in mGluR5 is detected in this model and MPEP is ineffective.

Key words: MPEP; mGluR5; nerve injury; upregulation; thermal hyperalgesia; VR1

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2272660-09$05.00/0

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