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β-Arrestins: Regulatory Role and Therapeutic Potential in Opioid and Cannabinoid Receptor-Mediated Analgesia
Open accessAbstract
Pain is a complex disorder with neurochemical and psychological components contributing to the severity, the persistence, and the difficulty in adequately treating the condition. Opioid and cannabinoids are two classes of analgesics that have been used to treat pain for centuries and are arguably the oldest of "pharmacological" interventions used by man. Unfortunately, they also produce several adverse side effects that can complicate pain management. Opioids and cannabinoids act at G protein-coupled receptors (GPCRs), and much of their effects are mediated by the mu-opioid receptor (MOR) and cannabinoid CB1 receptor (CB1R), respectively. These receptors couple to intracellular second messengers and regulatory proteins to impart their biological effects. In this chapter, we review the role of the intracellular regulatory proteins, β-arrestins, in modulating MOR and CB1R and how they influence the analgesic and side-effect profiles of opioid and cannabinoid drugs in vivo. This review of the literature suggests that the development of opioid and cannabinoid agonists that bias MOR and CB1R toward G protein signaling cascades and away from β-arrestin interactions may provide a novel mechanism by which to produce analgesia with less severe adverse effects.
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“Mutant mice that lacked arrestin 3 (b-arrestin 2) exhibited greater analgesia but significantly less antinociceptive tolerance, physical dependence, constipation, and respiratory suppression in response to morphine (Raehal and Bohn, 2014).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Raehal and Bohn, 2014
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Chapter 2. Genetics and Epigenetics of Addiction
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Chapter 37. Substance-Related Disorders in Adolescents
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Chapter 3. Epidemiology of Addiction
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“Furthermore, CB 1 receptor activation also initiates beta-arrestin 1 and 2 signaling (Raehal & Bohn, 2014), further increasing the complexity of CB 1 receptor-mediated intracellular activity.”
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BackgroundChapter 48. Trauma- and Stressor-Related Disorders
Fitzpatrick, S., Jarnecke, A. M., Back, S. E., Straus, E., Norman, S., & Hien, D. A. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb48 · Cited by 25
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Chapter 35. Prevention of Substance Use Disorders
Champion, K. E., Newton, N. C., & Teesson, M. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb35 · Cited by 24
Chapter 23. Cognitive-Behavioral Therapy
Carroll, K. M., & Kiluk, B. D. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb23 · Cited by 23
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Chapter 25. Motivational Enhancement
Shulman, M., Pruzan, K., & Carpenter, K. M. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb25 · Cited by 23
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“The binding of the opioids to these receptors also activates a second downstream pathway labeled as the beta‐arrestin pathway.[3] the Activation of the G‐protein pathway is responsible for analgesia, while the activation of the beta‐arrestin pathway contributes to unwanted effects of μ‐opioid receptor activation such…”
BackgroundKratom Dependence and Treatment Options: A Comprehensive Review of the Literature
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Class A and C GPCR Dimers in Neurodegenerative Diseases
Moreira, I. S., Caniceiro, A. B., Bueschbell, B., & Schiedel, A. C. (2022) · Current Neuropharmacology · doi:10.2174/1570159x20666220327221830 · Cited by 18
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“It is observed that mice that are genetically modified to knock out their beta‐arrestins display enhanced and prolonged morphine‐induced antinociception.[7] It is likely that the absence of beta‐arrestins in these mice leads to selective amplification of the analgesic pathway.”
BackgroundEvidence for the emergence of an opioid‐resistant respiratory rhythm following fentanyl overdose
Haouzi, P. A., Mellen, N. M., McCann, M. L., Sternick, M. E., Guck, D., & Tubbs, N. (2020) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2020.103428 · Cited by 19
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Zhang, Y., Williams, D. A., Zaidi, S. A., Yuan, Y., Braithwaite, A., Bilsky, E. J., Dewey, W. L., Akbarali, H. I., Streicher, J. M., & Selley, D. E. (2015) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00245 · Cited by 18
Goudra, B., Singh, P., & Lichtenstein, G. (2020) · Digestive Diseases and Sciences · doi:10.1007/s10620-020-06464-3 · Cited by 16
Fipps, D. C., Oesterle, T., & Kolla, B. P. (2024) · Seminars in Neurology · doi:10.1055/s-0044-1787571 · Cited by 16
“27”
Araldi, D., Bonet, I. J. M., Green, P. G., & Levine, J. D. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.1982-21.2021 · Cited by 15
New Insights Into Peptide Cannabinoids: Structure, Biosynthesis and Signaling
Riquelme-Sandoval, A., de Sá-Ferreira, C. O., Miyakoshi, L. M., & Hedin‐Pereira, C. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.596572 · Cited by 14
“Modulation of the CB1/CB2 Signaling Pathways Besides recruiting different G proteins, cannabinoid receptors can recruit other proteins for signaling, most prominently β-arrestin1 and -2, which mediate receptor desensitization, regulation of receptor sensitivity to acute agonists and receptor internalization (Breivogel…”
BackgroundHaddou, T. B., Malfacini, D., Calò, G., Aceto, M. D. G., Harris, L. S., Traynor, J. R., Coop, A., Schmidhammer, H., & Spetea, M. (2014) · Molecular Pain · doi:10.1186/1744-8069-10-48 · Cited by 13
“Over the past years, increased attention has been drawn to the understanding of intracellular signaling pathways that mediate the therapeutic and/or adverse effects of opioid agonists acting at the MOP receptor [42-44].”
BackgroundOpioids and Vitamin C: Known Interactions and Potential for Redox-Signaling Crosstalk
Newman, M. S., Connery, H., & Boyd, J. (2022) · Antioxidants · doi:10.3390/antiox11071267 · Cited by 13
“Accumulation of β-arrestin at MOR decreases signaling post-activation [91], ceasing this activity.”
BackgroundBedini, A., Cuna, E., Baiula, M., & Spampinato, S. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095114 · Cited by 10
“On top of that, it should be considered that robust physiological evidence for arrestin signaling from MOR affecting respiratory function is absent [30], and that several laboratories have been unable to repeat the primary result of reduced morphine respiratory depression in arrestin knockout mice [31].”
BackgroundKratom use disorder: a primer for primary care physicians
Groff, D., Stuckey, H. L., Philpott, C. D., Dyke, E. V., Silvis, M. L., Leong, S. L., & Bone, C. (2021) · Journal of Addictive Diseases · doi:10.1080/10550887.2021.1950263 · Cited by 10
The Development of Cannabinoids as Therapeutic Agents in the United States
Murray, C. H., Gannon, B. M., Winsauer, P. J., Cooper, Z. D., & Delatte, M. S. (2024) · Pharmacological Reviews · doi:10.1124/pharmrev.123.001121 · Cited by 10
Opioid Modulation of Neuronal Iron and Potential Contributions to NeuroHIV
Nash, B., Irollo, E., Brandimarti, R., & Meucci, O. (2020) · Methods in molecular biology · doi:10.1007/978-1-0716-0884-5_13 · Cited by 8
Jeong, B., Song, Y. P., Chung, J. Y., Park, K. C., Kim, J., So, I., & Hong, C. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00535.2022 · Cited by 7
Sheikh, S., Fernandez, R., Smotherman, C. R., Brailsford, J., Langaee, T. Y., Velasquez, E., Henson, M., Munson, T., Bertrand, A. H., Hendry, P. L., et al. (2023) · Clinical and Translational Science · doi:10.1111/cts.13634 · Cited by 6
“47 We found participants with the ARRB2 rs1045280 TT genotype had a higher proportion of participants in the CIP-RIOSORD medium and high-risk class groups (54.5”
BackgroundInfluentialPearl‐Dowler, L., Posa, L., López-Canul, M., Teggin, A., & Gobbi, G. (2023) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2023.110805 · Cited by 7
Sharma, A., Dunn, K. E., Schmid-Doyle, K., Dowell, S., Kim, N., Strain, E. C., & Bergeria, C. L. (2024) · Journal of Addiction Medicine · doi:10.1097/adm.0000000000001395 · Cited by 6
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“…showed enhanced hypothermia and antinociception, as well as reduced tolerance development following chronic administration (Nguyen et al., 2012; Raehal and Bohn, 2014); however, because traditional cannabinoid agonists function as unbiased ligands and cannot preferentially activate G…”
BackgroundInfluentialHuang, Y., Lu, S., Chen, Y., Feng, Y., & Lu, W. (2023) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-023-02697-x · Cited by 5
“…tolerance is linked to G protein uncoupling, MAP kinase-phosphorylated opioid receptors (Williams et al. 2013), endocytosis activated by β-arrestin (Raehal and Bohn 2014), opioid receptor endocytosis that fails to target lysosomes (Allouche et al. 2014), the heterodimerization of other receptors,…”
Chapter 47. Attention-Deficit/Hyperactivity Disorder
Wilens, T. E., & Kaminski, T. A. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb47 · Cited by 5
Larauche, M. H., Érchegyi, J., Miller, C. L., Sim, M., Rivier, J., Behan, D. P., & Taché, Y. (2022) · Peptides · doi:10.1016/j.peptides.2022.170881 · Cited by 4
“5 display enhanced and prolonged morphine-induced antinociception in spinal (tail flick) and supra-spinal (hot plate) responses to a noxious thermal stimulus [52,53,7,8,9].”
BackgroundRational design of Gi-biased CB1 agonist with reduced side effects
Liao, Y.-Y., Che, J., Yun-tao, G., Xue, J., Li, L., Wu, L.-L., Hu, J.-X., Hu, M.-T., Xie, L., Zhang, H., et al. (2026) · Cell · doi:10.1016/j.cell.2026.03.020 · Cited by 3
Gajic, P., Kovac, I., Lubinsky, G. T., & Knežević, N. N. (2026) · Cells · doi:10.3390/cells15100858 · Cited by 3
“…endogenous opioid release in the hypothalamus, amygdala, and prefrontal cortex may dampen HPA axis activation and reduces negative affect, indicating that acute exercise-driven opioid signaling may contribute to both hypoalgesia and transient reductions in perceived stress and anxiety [6,48].”
Chapter 20. Neurobiology and Treatment of Sedative-, Hypnotic-, and Anxiolytic-Related Disorders
Jones, J. L., VandenBerg, A., & Malcolm, R. J. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb20 · Cited by 3
Chapter 10. Neurobiology of Stimulants
Sofuoglu, M., DeVito, E. E., & Kosten, T. R. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb10 · Cited by 3
Chapter 14. Opioid Antagonist Treatment of Opioid-Related Disorders
Capata, M., & Hartwell, K. J. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb14 · Cited by 3
Perioperative Pain, Analgesics and Cancer-Related Outcomes: where do we Stand?
Ramirez, M. F., Rangel, F. P., & Cata, J. P. (2021) · Pain Management · doi:10.2217/pmt-2021-0070 · Cited by 3
Chapter 34. Nicotine and Public Health
Cummings, K. M., Borland, R., & Braak, D. C. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb34 · Cited by 3
Dezocine and Addiction: Friend or Foe?
Childers, W. E., Elokely, K. M., & Abou-Gharbia, M. A. (2025) · Pharmaceuticals · doi:10.3390/ph18030386 · Cited by 2
“…desensitization and internalization However, there is evidence that the beta2-arrestin pathway also plays a role in many of the adverse effects associated with opioid analgesics [24], including respiratory depression, constipation, and even addiction and dependence [25]. internalization [23].”
Chapter 4. Substance Use Disorder Diagnoses in DSM-5
Hasin, D. S., & Larson, F. R. R. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb04 · Cited by 2
Zangrandi, L., Fogli, B., Mutti, A., Staritzbichler, R., Most, V., Hildebrand, P. W., Heilbronn, R., & Schwarzer, C. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1484730 · Cited by 2
Wattiez, A., Walder, R. Y., Sande, C. M., White, S. R., & Hammond, D. L. (2017) · Molecular Pain · doi:10.1177/1744806917715210 · Cited by 2
Koob, G. F., Arends, M. A., McCracken, M. L., & Moal, M. L. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-816988-9.00001-1 · Cited by 2
Chapter 49. Schizophrenia Spectrum and Other Psychotic Disorders
Schwartz, E., Brunette, M. F., & Green, A. I. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb49 · Cited by 2
Chapter 18. Neurobiology of Nicotine and Tobacco
Gubner, N. R., & Benowitz, N. L. (2021) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9781615373970.kb18 · Cited by 2
Metadata
- Authors
- Raehal, K. M., & Bohn, L. M.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Raehal, Kirsten M.
- ORCID
- Bohn, Laura M.
- Venue
- Handbook of Experimental Pharmacology
- Publisher
- Springer Berlin Heidelberg
- Published
- 2013-11-05
- Volume
- 219
- Pages
- 427-443
- ISSN
- 0171-2004 (ISSN-L)
- 1865-0325
- PMC
- PMC4804701
- OpenAlex
- W78722479
- Cited by
- 154
- References
- 99
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 5 · 2023: 7 · 2022: 10 · 2021: 63 · 2020: 13 · 2019: 11 · 2018: 7 · 2017: 15 · 2016: 5 · 2015: 2 · 2014: 3
- FWCI
- 4.36
- Type
- book chapter
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Handbook of experimental pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (R01DA033073, R01DA031927)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Keywords
- beta-arrestin, mu-opioid receptor, CB1 receptor, opioid analgesia, cannabinoid analgesia, G protein-coupled receptors, biased agonists, G protein signaling, receptor internalization, pain management, opioid side effects
- MeSH terms
- beta-Arrestins, Analgesics, Analgesics, Opioid, Animals, Cannabinoids, Humans, Pain, Drug Design, Receptors, Opioid, mu, Arrestins, Receptors, G-Protein-Coupled, Receptor, Cannabinoid, CB1
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