BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) reveals the involvement of the transforming growth factor-beta family in pain modulation

J Neurosci. 2010 Jan 27;30(4):1502-11. doi: 10.1523/JNEUROSCI.2584-09.2010.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism
  • Activins / pharmacology
  • Afferent Pathways / metabolism*
  • Animals
  • Bone Morphogenetic Protein 7 / metabolism
  • Bone Morphogenetic Protein 7 / pharmacology
  • Cells, Cultured
  • Disease Models, Animal
  • Enkephalins / genetics
  • Enkephalins / metabolism
  • Hyperalgesia / genetics
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Narcotic Antagonists / pharmacology
  • Nociceptors / drug effects
  • Nociceptors / metabolism
  • Pain Measurement / methods
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Peripheral Nerves / metabolism*
  • Peripheral Nerves / physiopathology
  • Peripheral Nervous System Diseases / genetics
  • Peripheral Nervous System Diseases / metabolism*
  • Peripheral Nervous System Diseases / physiopathology
  • Pro-Opiomelanocortin / genetics
  • Pro-Opiomelanocortin / metabolism
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Receptors, Opioid, delta / genetics
  • Receptors, Opioid, delta / metabolism
  • Sciatic Neuropathy / genetics
  • Sciatic Neuropathy / metabolism
  • Sciatic Neuropathy / physiopathology
  • Signal Transduction / genetics
  • Spinal Cord / metabolism*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Up-Regulation / genetics


  • Bambi protein, mouse
  • Bone Morphogenetic Protein 7
  • Enkephalins
  • Membrane Proteins
  • Narcotic Antagonists
  • Protein Precursors
  • Receptors, Opioid, delta
  • Transforming Growth Factor beta
  • activin A
  • proenkephalin
  • Activins
  • Pro-Opiomelanocortin