Enhanced Morphine Analgesia in Mice Lacking β-Arrestin 2

TLDR

Morphine analgesia is mediated by the μ‑opioid receptor, a GPCR whose signaling is tightly regulated by receptor phosphorylation and interaction with β‑arrestins. Mice lacking β‑arrestin 2 exhibit markedly enhanced and prolonged morphine analgesia, indicating that β‑arrestin 2 mediates μ‑opioid receptor desensitization and that its inhibition could improve pain treatment and reduce tolerance.

Abstract

The ability of morphine to alleviate pain is mediated through a heterotrimeric guanine nucleotide binding protein (G protein)–coupled heptahelical receptor (GPCR), the μ opioid receptor (μOR). The efficiency of GPCR signaling is tightly regulated and ultimately limited by the coordinated phosphorylation of the receptors by specific GPCR kinases and the subsequent interaction of the phosphorylated receptors with β-arrestin 1 and β-arrestin 2. Functional deletion of the β-arrestin 2 gene in mice resulted in remarkable potentiation and prolongation of the analgesic effect of morphine, suggesting that μOR desensitization was impaired. These results provide evidence in vivo for the physiological importance of β-arrestin 2 in regulating the function of a specific GPCR, the μOR. Moreover, they suggest that inhibition of β-arrestin 2 function might lead to enhanced analgesic effectiveness of morphine and provide potential new avenues for the study and treatment of pain, narcotic tolerance, and dependence.