Role of β-arrestin-2 in short- and long-term opioid tolerance in the dorsal root ganglia

G-protein-biased agonists with reduced 0-arrestin-2 activation are being investigated as safer alternatives to clinically-used opioids. 0-arrestin-2 has been implicated in the mechanism of opioid-induced antinociceptive tolerance. Opioid-induced analgesic tolerance is classically considered as centrally-mediated, but recent reports implicate nociceptive dorsal root ganglia neurons as critical mediators in this process. Here, we investigated the role of 0-arrestin-2 in the mechanism of opioid tolerance in dorsal root ganglia nociceptive neurons using 0-arrestin-2 knockout mice and the G-protein-biased ?-opioid receptor agonist, TRV130. Whole-cell currentclamp electrophysiology experiments revealed that 15-18-h overnight exposure to 10 ?M morphine in vitro induced acute tolerance in 0-arrestin-2 wild-type but not knockout neurons. Furthermore, in wild-type neurons circumventing 0-arrestin-2 activation by overnight treatment with 200 nM TRV130 attenuated tolerance. Similarly, acute morphine tolerance in vivo in 0-arrestin-2 knockout mice was prevented in the warm-water tailwithdrawal assay. Treatment with 30 mg/kg TRV130 s.c. also inhibited acute antinociceptive tolerance in vivo in wild-type mice. Alternately, in 0-arrestin-2 knockout neurons tolerance induced by 7-day in vivo exposure to 50 mg morphine pellet was conserved. Likewise, 0-arrestin-2 deletion did not mitigate in vivo antinociceptive tolerance induced by 7-day exposure to 25 mg or 50 mg morphine pellet in both female or male mice, respectively. Consequently, these results indicated that 0-arrestin-2 mediates acute but not chronic opioid tolerance in dorsal root ganglia neurons and to antinociception in vivo. This suggests that opioid-induced antinociceptive tolerance may develop even in the absence of 0-arrestin-2 activation, and thus significantly affect the clinical utility of biased agonists.

Automated summary

The role of 0-arrestin-2 in opioid tolerance was investigated, showing its involvement in acute, but not chronic tolerance in dorsal root ganglia neurons and in vivo antinociception. These findings suggest that opioid-induced antinociceptive tolerance can develop even without 0-arrestin-2 activation, significantly impacting the clinical utility of biased agonists.