BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) reveals the involvement of the transforming growth factor-beta family in pain modulation.
Transforming growth factors-beta (TGF-betas) signal through type I and type II serine-threonine kinase receptor complexes. During ligand binding, type II receptors recruit and phosphorylate type I receptors, triggering downstream signaling. BAMBI [bone morphogenetic protein (BMP) and activin membrane-bound inhibitor] is a transmembrane pseudoreceptor structurally similar to type I receptors but lacks the intracellular kinase domain. BAMBI modulates negatively pan-TGF-beta family signaling; therefore, it can be used as an instrument for unraveling the roles of these cytokines in the adult CNS. BAMBI is expressed in regions of the CNS involved in pain transmission and modulation. The lack of BAMBI in mutant mice resulted in increased levels of TGF-beta signaling activity, which was associated with attenuation of acute pain behaviors, regardless of the modality of the stimuli (thermal, mechanical, chemical/inflammatory). The nociceptive hyposensitivity exhibited by BAMBI(-/-) mice was reversed by the opioid antagonist naloxone. Moreover, in a model of chronic neuropathic pain, the allodynic responses of BAMBI(-/-) mice also appeared attenuated through a mechanism involving delta-opioid receptor signaling. Basal mRNA and protein levels of precursor proteins of the endogenous opioid peptides proopiomelanocortin (POMC) and proenkephalin (PENK) appeared increased in the spinal cords of BAMBI(-/-). Transcript levels of TGF-betas and their intracellular effectors correlated directly with genes encoding opioid peptides, whereas BAMBI correlated inversely. Furthermore, incubation of spinal cord explants with activin A or BMP-7 increased POMC and/or PENK mRNA levels. Our findings identify TGF-beta family members as modulators of acute and chronic pain perception through the transcriptional regulation of genes encoding the endogenous opioids.
Tramullas
Mónica
M
Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain, Instituto de Formación e Investigación Marqués de Valdecilla, 39008 Santander, Spain.
Lantero
Aquilino
A
Díaz
Alvaro
A
Morchón
Néstor
N
Merino
David
D
Villar
Ana
A
Buscher
Dirk
D
Merino
Ramón
R
Hurlé
Juan M
JM
Izpisúa-Belmonte
Juan Carlos
JC
Hurlé
María A
MA
D028341:Activins / Q000378:metabolism / Q000494:pharmacology; D000344:Afferent Pathways / Q000378:metabolism*; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009292:Narcotic Antagonists / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010525:Peripheral Nerves / Q000378:metabolism* / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
C485672:Bambi protein, mouse; D055419:Bone Morphogenetic Protein 7; D004745:Enkephalins; D008565:Membrane Proteins; D009292:Narcotic Antagonists; D011498:Protein Precursors; D017465:Receptors, Opioid, delta; D016212:Transforming Growth Factor beta; C422405:activin A; C029992:proenkephalin; D028341:Activins; D011333:Pro-Opiomelanocortin