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

View ORCID ProfileKaran H. Muchhala, Joanna C. Jacob, View ORCID ProfileWilliam L. Dewey, View ORCID ProfileHamid I. Akbarali
doi: https://doi.org/10.1101/2020.11.15.383620
Karan H. Muchhala
aDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 East Clay St, Richmond, VA 23298, USA
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Joanna C. Jacob
aDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 East Clay St, Richmond, VA 23298, USA
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William L. Dewey
aDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 East Clay St, Richmond, VA 23298, USA
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Hamid I. Akbarali
aDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, 1112 East Clay St, Richmond, VA 23298, USA
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  • For correspondence: hamid.akbarali@vcuhealth.org
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Abstract

β-arrestin-2 has been implicated in the mechanism of opioid-induced antinociceptive tolerance. G-protein-biased agonists with reduced β-arrestin-2 activation are being investigated as safer alternatives to clinically-used opioids. Opioid-induced analgesic tolerance is classically considered as centrally-mediated, but recent reports implicate nociceptive dorsal root ganglia (DRG) neurons as critical mediators in this process. Here, we investigated the role of β-arrestin-2 in the mechanism of opioid tolerance in DRG nociceptive neurons using β-arrestin-2 knockout mice and the G-protein-biased μ-opioid receptor agonist, TRV130. Whole-cell current-clamp electrophysiology experiments revealed that 15-18-hour overnight exposure to 10 μM morphine in vitro induced acute tolerance in β-arrestin-2 wild-type but not knockout DRG neurons. Furthermore, in wild-type DRG neurons circumventing β-arrestin-2 activation by overnight treatment with 200 nM TRV130 attenuated tolerance. Similarly, in β-arrestin-2 knockout male mice acute antinociceptive tolerance induced by 100 mg/kg morphine s.c. was prevented in the warm-water tail-withdrawal assay. Treatment with 30 mg/kg TRV130 s.c. also inhibited antinociceptive tolerance in wild-type mice. Alternately, in β-arrestin-2 knockout DRG neurons tolerance induced by 7-day in vivo exposure to 50 mg morphine pellet was conserved. Likewise, β-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 β-arrestin-2 mediates acute but not chronic opioid tolerance in DRG neurons and to antinociception. This suggests that opioid-induced antinociceptive tolerance may develop even in the absence of β-arrestin-2 activation, and thus significantly affect the clinical utility of biased agonists.

Competing Interest Statement

The authors have declared no competing interest.

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  • Declarations of interest: none

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 15, 2020.
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Role of β-arrestin-2 in short- and long-term opioid tolerance in the dorsal root ganglia
Karan H. Muchhala, Joanna C. Jacob, William L. Dewey, Hamid I. Akbarali
bioRxiv 2020.11.15.383620; doi: https://doi.org/10.1101/2020.11.15.383620
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Role of β-arrestin-2 in short- and long-term opioid tolerance in the dorsal root ganglia
Karan H. Muchhala, Joanna C. Jacob, William L. Dewey, Hamid I. Akbarali
bioRxiv 2020.11.15.383620; doi: https://doi.org/10.1101/2020.11.15.383620

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