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TGF-beta and Opioid Receptor Signaling Crosstalk Results in Improvement of Endogenous and Exogenous Opioid Analgesia under Pathological Pain Conditions

Abstract : Transforming growth factor-beta 1 (TGF-beta 1) protects against neuroinflammatory events underlying neuropathic pain. TGF-beta signaling enhancement is a phenotypic characteristic of mice lacking the TGF-beta 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-beta 1. BAMBI-KO mice were subjected to neuropathic pain by sciatic nerve crash injury (SNI). Gene (PCR) and protein (Western blot) expressions of mu- and delta-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 mu-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-beta 1 infusion prevented pain development after SNI. The antiallodynic effect of TGF-beta 1 was naloxone-sensitive. In conclusion, modulation of the endogenous opioid system by TGF-beta signaling improves the analgesic effectiveness of exogenous and endogenous opioids under pathological pain conditions.
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https://hal-cnrs.archives-ouvertes.fr/hal-03292697
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Submitted on : Tuesday, July 20, 2021 - 3:23:11 PM
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Aquilino Lantero, Monica Tramullas, Fuencisla Pilar-Cuellar, Elsa Valdizan, Rosa Santillan, et al.. TGF-beta and Opioid Receptor Signaling Crosstalk Results in Improvement of Endogenous and Exogenous Opioid Analgesia under Pathological Pain Conditions. Journal of Neuroscience, Society for Neuroscience, 2014, 34 (15), pp.5385-5395. ⟨10.1523/JNEUROSCI.4405-13.2014⟩. ⟨hal-03292697⟩

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