Neuropathic pain is one of the most disabling forms of
chronic pain and it is characterized by
hyperalgesia and
allodynia linked to an aberrant processing of
pain transmission and to
neuroinflammation. Transforming growth factor-β1 (TGF-β1) is an anti-inflammatory
cytokine, which protects against
neuroinflammation. It has been demonstrated that TGF-β1 and
opioid receptors signalling crosstalk results in an improvement of endogenous
opioid analgesia, but it is not known whether mu
opioid peptide receptor (MOPr) or delta
opioid peptide receptor (DOPr) agonists can positively modulate TGF-β1 pathway. In the present study, we examined the correlation between anti-allodynic effect of LP2, a dual-target MOPr/DOPr agonist, and TGF-β1 signalling in the chronic constriction injury (CCI) model. We detected a significant decrease of active TGF-β1 and of its type II receptor TGFβ-R2 levels in the spinal cord from CCI rats and a selective deficit of TGF-β1 in microglia cells both at days 11 and 21 post-
ligature, as assessed by immunofluorescence analysis. LP2, when administered from the 11 days post-
ligature to 21 days, was able to reduce CCI-induced
mechanical allodynia by rescue of TGF-β1 and TGFβ-R2 levels. Our data suggest that the rescue of TGF-β1 signalling by dual-target MOPr/DOPr agonist LP2 could be mediated by DOPr activation in spinal microglia, thus the dual-target approach could represent a novel pharmacological approach to increase the
analgesic efficacy of MOPr agonists.