A role of the ubiquitin-proteasome system in neuropathic pain.
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.
Moss
Andrew
A
Department of Preclinical Veterinary Sciences, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Summerhall, Edinburgh EH9 1QH, United Kingdom.
Blackburn-Munro
Gordon
G
Garry
Emer M
EM
Blakemore
James A
JA
Dickinson
Tracey
T
Rosie
Roberta
R
Mitchell
Rory
R
Fleetwood-Walker
Susan M
SM
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004195:Disease Models, Animal; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology; D017403:In Situ Hybridization; D007278:Injections, Spinal; D007478:Iontophoresis; D008026:Ligation; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D010147:Pain Measurement; D020671:Posterior Horn Cells / Q000187:drug effects / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects; D020426:Sciatic Neuropathy / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase
D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D025801:Ubiquitin; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex