Role of β-Arrestin-2 in Opioid Tolerance and Opioidergic & α-2 Adrenergic Analgesic Synergism

Background Fentanyl (FEN) is a synthetic opioid with high affinity for µ-opioid receptors (MOR). Tolerance development is a significant problem that limits the effective use of opioids. Dexmedetomidine (DEX) and xylazine (XYL) are α-2 adrenoceptor (AR) agonists with sedative and analgesic effects. In our previous study, we demonstrated that these agents exhibit analgesic synergy with FEN. β-arrestin-2 mediates the desensitization and internalization of G protein-coupled opioid receptors. In this study, we aimed to investigate the role of β-arrestin-2 in opioid tolerance and opioidergic-α-2 adrenergic analgesia synergism. Methods Wistar albino rats were divided into six groups: control, FEN, DEX, XYL, FEN + DEX, and FEN + XYL. The groups received intraperitoneal injections in the morning and evening on the first two days and only in the morning on the third day. The rats were sacrificed on the third day, and their spinal cords were removed. The tissues were subjected to immunohistochemical analysis to assess β-arrestin-2 immunoreactivity. Results The spinal cords of the groups appeared morphologically normal. Compared to the control group, β-arrestin-2 immunoreactivity was significantly reduced in the FEN + DEX and FEN + XYL groups. Although not statistically significant, there was a trend toward decreased β-arrestin-2 immunoreactivity in the other groups. According to our study results, β-arrestin-2 caused receptor desensitization without altering MOR levels. Conclusions This important protein induces tolerance by affecting MORs. It also affects α-2 ARs, affecting opioidergic-α-2 adrenergic synergism.