Proteasome inhibitor MG132 modulates inflammatory pain by central mechanisms in adjuvant arthritis.
OBJECTIVE
In rheumatoid arthritis (RA), pain and inflammation are initial symptoms followed by various degrees of bone and cartilage destruction. Previously, we have shown that reversible proteasome inhibitor MG132 attenuates pain and joint inflammation in a rat model of adjuvant-arthritis. Our present study aims to study the effects of MG132 on molecular changes in the dorsal root ganglia (DRG) and in the spinal cord (SC) using the same animal model.


METHODS
Arthritis was induced by heat-killed Mycobacterium butyricum in rats. The expression of substance P (SP) was analyzed by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in DRG and in the SC. The nuclear factor-κB (NF-κB) DNA-binding activity in the SC was analyzed by electromobility shift assay.


RESULTS
Arthritic rats treated daily with MG132 demonstrated a marked reduction of SP gene expression in the DRG and number of SP-positive cells was reduced. In the spinal cord of arthritic rats elevated SP messenger RNA levels were normalized and NF-κB-DNA-binding activity was down-regulated in arthritic rats treated with MG132.


CONCLUSIONS
Our results indicate that proteasome inhibitor MG132 attenuates pain in adjuvant arthritis by targeting the sensory neuropeptide substance P in the peripheral and central nervous systems. These effects may be mediated through the inhibition of NF-κB activation.
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Aisha Siddiqah
AS
Ahmed
Department of Neurobiology, Care Sciences and Society, Center for Family and Community Medicine, Karolinska Institutet, Huddinge, Sweden.
Mahmood
M
Ahmed
Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Jian
J
Li
Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Harvest F
HF
Gu
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Georgy
G
Bakalkin
Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
André
A
Stark
Department of Medicine, Center for molecular medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Helena Erlandsson
HE
Harris
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000382:microbiology; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000201:enzymology; D007976:Leupeptins / Q000494:pharmacology*; D009161:Mycobacterium; D016328:NF-kappa B / Q000378:metabolism; D010146:Pain / Q000201:enzymology / Q000382:microbiology / Q000517:prevention & control*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology; D013373:Substance P / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D007976:Leupeptins; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D013373:Substance P; D004247:DNA; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
pain; rheumatoid arthritis; spinal cord; substance P; ubiquitin proteasome system