Targeted inhibition of mu-opioid receptors in neuronal subpopulations by membrane-tethered Naloxo-DART antagonists

J. Sanchez; A. Bonifazi; S. Groom; M. O. Sambrook; G. A. Camacho-Hernandez; E. J. Kuijer; S. Karimi; K. U. Therese; M. Hauge Pedersen; C. Rauffenbart; M. Canals; A. H. Newman; C. P. Bailey; J. A. Javitch; J. R. Lane

doi:10.1016/j.chembiol.2025.11.002

Targeted inhibition of mu-opioid receptors in neuronal subpopulations by membrane-tethered Naloxo-DART antagonists

J. Sanchez
, A. Bonifazi
, S. Groom
, M. O. Sambrook
, G. A. Camacho-Hernandez
, E. J. Kuijer
, S. Karimi
, K. U. Therese
, M. Hauge Pedersen
, C. Rauffenbart
, M. Canals
, A. H. Newman
, C. P. Bailey
, J. A. Javitch
, J. R. Lane

Pharmacology & Toxicology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Opioid receptors are expressed in virtually all neural loci contributing to the experience of pain. Due to this widespread expression, the contribution of specific cell types to the analgesic properties and deleterious side effects of opioids remains incompletely understood. Linking the activity of specific receptors in defined cells to behavioral or physiological processes remains a major challenge of translational pharmacology. In this study, we describe the development of drugs acutely restricted by membrane tethering (DART) antagonists that contain an antagonist naloxone moiety linked to a Halo-tag reactive group. The optimized Naloxo-DART displayed robust blockade of a MOR agonist only when cells co-expressed a Halo-tagged membrane tether. We use the Naloxo-DART delivered in vivo to selectively block MORs in locus coeruleus neurons in brain slide preparations. The Naloxo-DART provides a powerful approach for elucidating the physiological roles of MORs expressed in specific neuronal populations with acute spatiotemporal control.

Original language	English (US)
Pages (from-to)	1473-1485.e9
Journal	Cell Chemical Biology
Volume	32
Issue number	12
DOIs	https://doi.org/10.1016/j.chembiol.2025.11.002
State	Published - Dec 18 2025

Keywords

DART
G-protein-coupled receptor
chemogenetics
drugs acutely restricted by membrane tethering
opioid receptor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2025.11.002

Cite this

Sanchez, J., Bonifazi, A., Groom, S., Sambrook, M. O., Camacho-Hernandez, G. A., Kuijer, E. J., Karimi, S., Therese, K. U., Hauge Pedersen, M., Rauffenbart, C., Canals, M., Newman, A. H., Bailey, C. P., Javitch, J. A., & Lane, J. R. (2025). Targeted inhibition of mu-opioid receptors in neuronal subpopulations by membrane-tethered Naloxo-DART antagonists. Cell Chemical Biology, 32(12), 1473-1485.e9. https://doi.org/10.1016/j.chembiol.2025.11.002

Sanchez, J, Bonifazi, A, Groom, S, Sambrook, MO, Camacho-Hernandez, GA, Kuijer, EJ, Karimi, S, Therese, KU, Hauge Pedersen, M, Rauffenbart, C, Canals, M, Newman, AH, Bailey, CP, Javitch, JA & Lane, JR 2025, 'Targeted inhibition of mu-opioid receptors in neuronal subpopulations by membrane-tethered Naloxo-DART antagonists', Cell Chemical Biology, vol. 32, no. 12, pp. 1473-1485.e9. https://doi.org/10.1016/j.chembiol.2025.11.002

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abstract = "Opioid receptors are expressed in virtually all neural loci contributing to the experience of pain. Due to this widespread expression, the contribution of specific cell types to the analgesic properties and deleterious side effects of opioids remains incompletely understood. Linking the activity of specific receptors in defined cells to behavioral or physiological processes remains a major challenge of translational pharmacology. In this study, we describe the development of drugs acutely restricted by membrane tethering (DART) antagonists that contain an antagonist naloxone moiety linked to a Halo-tag reactive group. The optimized Naloxo-DART displayed robust blockade of a MOR agonist only when cells co-expressed a Halo-tagged membrane tether. We use the Naloxo-DART delivered in vivo to selectively block MORs in locus coeruleus neurons in brain slide preparations. The Naloxo-DART provides a powerful approach for elucidating the physiological roles of MORs expressed in specific neuronal populations with acute spatiotemporal control.",

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AU - Camacho-Hernandez, G. A.

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AU - Hauge Pedersen, M.

AU - Rauffenbart, C.

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AU - Newman, A. H.

AU - Bailey, C. P.

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AU - Lane, J. R.

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AB - Opioid receptors are expressed in virtually all neural loci contributing to the experience of pain. Due to this widespread expression, the contribution of specific cell types to the analgesic properties and deleterious side effects of opioids remains incompletely understood. Linking the activity of specific receptors in defined cells to behavioral or physiological processes remains a major challenge of translational pharmacology. In this study, we describe the development of drugs acutely restricted by membrane tethering (DART) antagonists that contain an antagonist naloxone moiety linked to a Halo-tag reactive group. The optimized Naloxo-DART displayed robust blockade of a MOR agonist only when cells co-expressed a Halo-tagged membrane tether. We use the Naloxo-DART delivered in vivo to selectively block MORs in locus coeruleus neurons in brain slide preparations. The Naloxo-DART provides a powerful approach for elucidating the physiological roles of MORs expressed in specific neuronal populations with acute spatiotemporal control.

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Targeted inhibition of mu-opioid receptors in neuronal subpopulations by membrane-tethered Naloxo-DART antagonists

Abstract

Keywords

ASJC Scopus subject areas

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