The Rac GTPase-activating bacterial protein toxin CNF1 induces analgesia up-regulating mu-opioid receptors.
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.
Pavone
Flaminia
F
CNR, Institute of Neuroscience, Psychobiology and Psychopharmacology, via del Fosso di Fiorano 64, 00143 Roma, Italy.
Luvisetto
Siro
S
Marinelli
Sara
S
Straface
Elisabetta
E
Fabbri
Alessia
A
Falzano
Loredana
L
Fiorentini
Carla
C
Malorni
Walter
W
D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D029968:Escherichia coli Proteins / Q000494:pharmacology* / Q000627:therapeutic use*; D005557:Formaldehyde / Q000009:adverse effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D010146:Pain / Q000139:chemically induced / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics; D054462:p21-Activated Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000700:Analgesics; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D016328:NF-kappa B; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; C060296:cytotoxic necrotizing factor type 1; D005557:Formaldehyde; D009270:Naloxone; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins