The simultaneous activation of μ- and δ-opioid receptors by (−)-2S-LP2 rescues allodynia with the contribution of TGF-β1 signaling in a rat chronic constriction injury model

In neuropathic pain (NP), a dysregulation of glial functions in the central and peripheral nervous systems has been described, and the balance between pro-inflammatory and anti-inflammatory mediators is lost in the transition from acute to chronic pain. This raises the possibility to resolve pain via the induction of anti-inflammatory cytokines that have a protective role against neuroinflammatory events. Transforming growth factor-β1 (TGF-β1), an anti‐inflammatory cytokine is able to counteract the development of chronic NP. Given the correlation between opioid agonists and TGF-β1 pathway, here we describe the pharmacological profile of the dual-target μ-opioid receptor (MOR)/δ-opioid receptor (DOR) agonist (−)-2S-LP2. (−)-2S-LP2, given intraperitoneally at a dose of 0.7 mg/kg, significantly mitigated mechanical allodynia induced by chronic constriction injury in rats. This antiallodynic effect was sensitive to subcutaneous (s.c.) injection of either the MOR-selective antagonist naloxonazine (NLX, 10 mg/kg) or the DOR-selective antagonist naltrindole (NTD, 3 mg/kg), alone or when combined, demonstrating that (−)-2S-LP2 interacted simultaneously with both MOR and DOR. At mRNA or protein level, a positive effect on TGF-β1 and its receptor TGFβ-R2 expression were found and (−)-2S-LP2 also modulated the expression of spinal TGF-β1 pathway via co‐targeting MOR/DOR. Thus, the dual‐target profile of the MOR/DOR agonist (−)-2S-LP2 exerts its analgesic efficacy by rescue of TGF-β1 and could represent a novel pharmacological tool able to increase anti-inflammatory cytokines in pain conditions such as NP associated with an imbalance between inflammatory and anti-inflammatory cytokines.