TGF-β and opioid receptor signaling crosstalk results in improvement of endogenous and exogenous opioid analgesia under pathological pain conditions.
Transforming growth factor-β1 (TGF-β1) protects against neuroinflammatory events underlying neuropathic pain. TGF-β signaling enhancement is a phenotypic characteristic of mice lacking the TGF-β pseudoreceptor BAMBI (BMP and activin membrane-bound inhibitor), which leads to an increased synaptic release of opioid peptides and to a naloxone-reversible hypoalgesic/antiallodynic phenotype. Herein, we investigated the following: (1) the effects of BAMBI deficiency on opioid receptor expression, functional efficacy, and analgesic responses to endogenous and exogenous opioids; and (2) the involvement of the opioid system in the antiallodynic effect of TGF-β1. BAMBI-KO mice were subjected to neuropathic pain by sciatic nerve crash injury (SNI). Gene (PCR) and protein (Western blot) expressions of μ- and δ-opioid receptors were determined in the spinal cord. The inhibitory effects of agonists on the adenylyl cyclase pathway were investigated. Two weeks after SNI, wild-type mice developed mechanical allodynia and the functionality of μ-opioid receptors was reduced. By this time, BAMBI-KO mice were protected against allodynia and exhibited increased expression and function of opioid receptors. Four weeks after SNI, when mice of both genotypes had developed neuropathic pain, the analgesic responses induced by morphine and RB101 (an inhibitor of enkephalin-degrading enzymes, which increases the synaptic levels of enkephalins) were enhanced in BAMBI-KO mice. Similar results were obtained in the formalin-induced chemical-inflammatory pain model. Subcutaneous TGF-β1 infusion prevented pain development after SNI. The antiallodynic effect of TGF-β1 was naloxone-sensitive. In conclusion, modulation of the endogenous opioid system by TGF-β signaling improves the analgesic effectiveness of exogenous and endogenous opioids under pathological pain conditions.
Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain, Instituto de Formación e Investigación Marqués de Valdecilla, 39011 Santander, Spain, Instituto de Biomedicina y Biotecnología de Cantabria IBBTEC, 39011 Santander, Spain, Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Spain, Departamento de Anestesiología y Reanimación, Hospital Universitario Valdecilla, Santander, Spain, Pharmaleads SAS, 75013 Paris, France, and Université Paris-Descartes, 75006 Paris, France.
Aquilino
A
Lantero
Mónica
M
Tramullas
Fuencisla
F
Pílar-Cuellar
Elsa
E
Valdizán
Rosa
R
Santillán
Bernard P
BP
Roques
María A
MA
Hurlé
D000067956:Adenylyl Cyclase Inhibitors; D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004220:Disulfides / Q000494:pharmacology / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D055104:Infusions, Subcutaneous; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology* / Q000627:therapeutic use; D009270:Naloxone / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000378:metabolism / Q000473:pathology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D000067956:Adenylyl Cyclase Inhibitors; D000701:Analgesics, Opioid; C485672:Bambi protein, mouse; D004220:Disulfides; D008565:Membrane Proteins; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D016212:Transforming Growth Factor beta; C074024:RB 101; D009270:Naloxone; D010649:Phenylalanine; D009020:Morphine
BAMBI; RB101; TGF-β; inflammatory pain; morphine; neuropathic pain