Exploration of beta-arrestin isoform signaling pathways in delta opioid receptor agonist-induced convulsions

The delta-opioid receptor (delta OR) has been considered as a therapeutic target in multiple neurological and neuropsychiatric disorders particularly as delta OR agonists are deemed safer alternatives relative to the more abuse-liable mu-opioid receptor drugs. Clinical development of delta OR agonists, however, has been challenging in part due to the seizure-inducing effects of certain delta OR agonists. Especially agonists that resemble the delta OR-selective agonist SNC80 have well-established convulsive activity. Close inspection suggests that many of those seizurogenic delta OR agonists efficaciously recruit beta-arrestin, yet surprisingly, SNC80 displays enhanced seizure activity in beta-arrestin 1 knockout mice. This finding led us to hypothesize that perhaps beta-arrestin 1 is protective against, whereas beta-arrestin 2 is detrimental for delta OR-agonist-induced seizures. To investigate our hypothesis, we characterized three different delta OR agonists (SNC80, ADL5859, ARM390) in cellular assays and in vivo in wild-type and beta-arrestin 1 and beta-arrestin 2 knockout mice for seizure activity. We also investigated downstream kinases associated with beta-arrestin-dependent signal transduction. We discovered that delta OR agonist-induced seizure activity strongly and positively correlates with beta-arrestin 2 efficacy for the agonist, but that indirect inhibition of ERK activation using the MEK inhibitor SL327 did not inhibit seizure potency and duration. Inhibition of the PI3K/AKT/mTOR signaling with honokiol but not PQR530, attenuated SNC80 seizure duration in beta-arrestin 1 knockout, but honokiol did not reduce SNC80-induced seizures in wild-type mice. Ultimately, our results indicate that beta-arrestin 2 is correlated with delta OR agonist-induced seizure intensity, but that global beta-arrestin 1 knockout mice are a poor model system to investigate their mechanism of action.

Automated summary

The study found that beta-arrestin 2 is positively correlated with the intensity of delta OR agonist-induced seizures, but global beta-arrestin 1 knockout mice are not an ideal model system to investigate their mechanism of action.