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The Journal of Neuroscience, February 15, 2002, 22(4):1363-1372

A Role of the Ubiquitin-Proteasome System in Neuropathic Pain

Andrew Moss¹, Gordon Blackburn-Munro¹, Emer M. Garry¹, James A. Blakemore¹, Tracey Dickinson¹, Roberta Rosie¹, Rory Mitchell², and Susan M. Fleetwood-Walker¹

¹ Department of Preclinical Veterinary Sciences, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Summerhall, Edinburgh EH9 1QH, United Kingdom, and ² Medical Research Council Membrane and Adapter Proteins Cooperative Group and Membrane Biology Group, Division of Biomedical and Clinical Laboratory Sciences, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom

Neuropathic pain (characterized by hyperalgesia and allodynia to mechanical and thermal stimuli) causes cellular changes in spinal dorsal horn neurons, some of which parallel those in synaptic plasticity associated with learning. Ubiquitin C-terminal hydrolase (UCH) appears to play a key role in long-term facilitation in Aplysia. The cooperation of UCH with the proteolytic enzyme complex known as the proteasome is required for the degradation of a number of signaling molecules within the cell that may remove normal restraints on synaptic plasticity. We have used electrophysiology, in situ hybridization histochemistry, semiquantitative RT-PCR, Western blotting, and in vivo behavioral reflex analysis to investigate the ubiquitin-proteasome system in a model of neuropathic pain. In neuropathic animals, ionophoretic application of selective proteasome inhibitors attenuated dorsal horn neuron firing evoked by normally innocuous brush or cold stimuli and by noxious mustard oil stimuli. In control animals, only mustard oil-evoked responses were inhibited. Intrathecal administration of proteasome inhibitors attenuated hyperalgesia and allodynia in neuropathic rats. Expression of UCH-L1 (a rat homolog of Aplysia neuronal UCH and of the human UCH-L1, also known as PGP 9.5) and its mRNA were selectively increased within the ipsilateral dorsal horn of neuropathic rats, supporting the idea of a role for the ubiquitin-proteasome system in nociceptive processing. Proteasome inhibitors selectively attenuate allodynic and hyperalgesic responses in neuropathic pain, with some reduction in normal nociceptive, but not non-nociceptive responses, and potentially represent a novel therapeutic strategy for neuropathic pain.

Key words: neuropathic pain; spinal cord; proteasome; ubiquitination; hyperalgesia; allodynia

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2241363-10$05.00/0

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