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The Rac GTPase-activating bacterial protein toxin CNF1 induces analgesia up-regulating mu-opioid receptors.
- Source :
-
Pain [Pain] 2009 Sep; Vol. 145 (1-2), pp. 219-29. Date of Electronic Publication: 2009 Jul 15. - Publication Year :
- 2009
-
Abstract
- Cytotoxic Necrotizing Factor 1 (CNF1) is a protein toxin from Escherichia coli that constitutively activates the Rho, Rac and Cdc42 GTPases. These regulatory proteins oscillate between a cytosolic GDP-bound inactive form and a membrane-linked GTP-bound active form, orchestrating the actin cytoskeleton assembly and dynamics. We herein describe, for the first time, the ability of CNF1 to potently counteract the formalin-induced inflammatory pain in mice. The analgesic response due to CNF1 requires both the sustained activation of the Rac GTPase, with consequent cerebral actin cytoskeleton remodeling, and the up-regulation of the mu-opioid receptors (MORs), the most important receptors controlling pain perception. The crucial role of Rac is proved by the lack of analgesic activity in mice challenged with a recombinant CNF1, in which the enzymatic activity was abolished by substituting serine with cysteine at position 866. The importance of MORs is proved by the inability of CNF1 to induce any analgesic effect in MORs knockout mice and by the ability of naloxone to antagonize the analgesic effects. Furthermore, it is worth noting that the analgesic effect in mice occurs after both peripheral and central administration of CNF1. Hence, taken altogether, our findings provide new insights into the comprehension of intracellular mechanisms involved in pain modulation, and indicate this bacterial protein toxin as a novel tool in the field of pain control. Conceivably, this might pave the way for new therapeutic strategies.
- Subjects :
- Animals
Cell Line, Tumor
Cerebellum drug effects
Cerebellum metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Inhibitors pharmacology
Formaldehyde adverse effects
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
NF-kappa B metabolism
Naloxone pharmacology
Narcotic Antagonists pharmacology
Neuroblastoma pathology
Pain chemically induced
Pain pathology
Pain Measurement drug effects
Receptors, Opioid, mu deficiency
Signal Transduction drug effects
Signal Transduction genetics
Time Factors
Transfection methods
Up-Regulation genetics
p21-Activated Kinases metabolism
rac GTP-Binding Proteins metabolism
rho GTP-Binding Proteins metabolism
Analgesics therapeutic use
Bacterial Toxins pharmacology
Bacterial Toxins therapeutic use
Escherichia coli Proteins pharmacology
Escherichia coli Proteins therapeutic use
Receptors, Opioid, mu metabolism
Up-Regulation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1872-6623
- Volume :
- 145
- Issue :
- 1-2
- Database :
- MEDLINE
- Journal :
- Pain
- Publication Type :
- Academic Journal
- Accession number :
- 19608345
- Full Text :
- https://doi.org/10.1016/j.pain.2009.06.026