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.