Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids

Ning Sheng Cai; César Quiroz; Jordi Bonaventura; Alessandro Bonifazi; Thomas O. Cole; Julia Purks; Amy S. Billing; Ebonie Massey; Michael Wagner; Eric D. Wish; Xavier Guitart; William Rea; Sherry Lam; Estefanía Moreno; Verònica Casadó-Anguera; Aaron D. Greenblatt; Arthur E. Jacobson; Kenner C. Rice; Vicent Casadó; Amy H. Newman; John W. Winkelman; Michael Michaelides; Eric Weintraub; Nora D. Volkow; Annabelle M. Belcher; Sergi Ferré

doi:10.1172/JCI126912

Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids

Ning Sheng Cai
, César Quiroz
, Jordi Bonaventura
, Alessandro Bonifazi
, Thomas O. Cole
, Julia Purks
, Amy S. Billing
, Ebonie Massey
, Michael Wagner
, Eric D. Wish
, Xavier Guitart
, William Rea
, Sherry Lam
, Estefanía Moreno
, Verònica Casadó-Anguera
, Aaron D. Greenblatt
, Arthur E. Jacobson
, Kenner C. Rice
, Vicent Casadó
, Amy H. Newman

John W. Winkelman, Michael Michaelides, Eric Weintraub, Nora D. Volkow, Annabelle M. Belcher, Sergi Ferré

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

57 Scopus citations

Abstract

Identifying nonaddictive opioid medications is a high priority in medical science, but μ-opioid receptors (MORs) mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of MORs with galanin Gal1 receptors (Gal1Rs), rendering a profound decrease in the potency of methadone. This finding was explained by the weaker proficiency of methadone in activating the dopaminergic system as compared with morphine and predicted a dissociation of the therapeutic and euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-reports of feeling “high” in methadone-medicated patients. These results suggest that μ-opioid-Gal1R heteromers mediate the dopaminergic effects of opioids. The results further suggest a lower addictive liability of some opioids, such as methadone, due to their selective low potency for the μ-opioid-Gal1R heteromer.

Original language	English (US)
Pages (from-to)	2730-2744
Number of pages	15
Journal	Journal of Clinical Investigation
Volume	129
Issue number	7
DOIs	https://doi.org/10.1172/JCI126912
State	Published - 2019
Externally published	Yes

ASJC Scopus subject areas

General Medicine

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Cai, N. S., Quiroz, C., Bonaventura, J., Bonifazi, A., Cole, T. O., Purks, J., Billing, A. S., Massey, E., Wagner, M., Wish, E. D., Guitart, X., Rea, W., Lam, S., Moreno, E., Casadó-Anguera, V., Greenblatt, A. D., Jacobson, A. E., Rice, K. C., Casadó, V., ... Ferré, S. (2019). Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids. Journal of Clinical Investigation, 129(7), 2730-2744. https://doi.org/10.1172/JCI126912

Cai, NS, Quiroz, C, Bonaventura, J, Bonifazi, A, Cole, TO, Purks, J, Billing, AS, Massey, E, Wagner, M, Wish, ED, Guitart, X, Rea, W, Lam, S, Moreno, E, Casadó-Anguera, V, Greenblatt, AD, Jacobson, AE, Rice, KC, Casadó, V, Newman, AH, Winkelman, JW, Michaelides, M, Weintraub, E, Volkow, ND, Belcher, AM & Ferré, S 2019, 'Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids', Journal of Clinical Investigation, vol. 129, no. 7, pp. 2730-2744. https://doi.org/10.1172/JCI126912

@article{d7f1b2bada0147a788319bac65dcc7cb,

title = "Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids",

abstract = "Identifying nonaddictive opioid medications is a high priority in medical science, but μ-opioid receptors (MORs) mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of MORs with galanin Gal1 receptors (Gal1Rs), rendering a profound decrease in the potency of methadone. This finding was explained by the weaker proficiency of methadone in activating the dopaminergic system as compared with morphine and predicted a dissociation of the therapeutic and euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-reports of feeling “high” in methadone-medicated patients. These results suggest that μ-opioid-Gal1R heteromers mediate the dopaminergic effects of opioids. The results further suggest a lower addictive liability of some opioids, such as methadone, due to their selective low potency for the μ-opioid-Gal1R heteromer.",

author = "Cai, \{Ning Sheng\} and C{\'e}sar Quiroz and Jordi Bonaventura and Alessandro Bonifazi and Cole, \{Thomas O.\} and Julia Purks and Billing, \{Amy S.\} and Ebonie Massey and Michael Wagner and Wish, \{Eric D.\} and Xavier Guitart and William Rea and Sherry Lam and Estefan{\'i}a Moreno and Ver{\`o}nica Casad{\'o}-Anguera and Greenblatt, \{Aaron D.\} and Jacobson, \{Arthur E.\} and Rice, \{Kenner C.\} and Vicent Casad{\'o} and Newman, \{Amy H.\} and Winkelman, \{John W.\} and Michael Michaelides and Eric Weintraub and Volkow, \{Nora D.\} and Belcher, \{Annabelle M.\} and Sergi Ferr{\'e}",

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year = "2019",

doi = "10.1172/JCI126912",

language = "English (US)",

volume = "129",

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AU - Cai, Ning Sheng

AU - Quiroz, César

AU - Bonaventura, Jordi

AU - Bonifazi, Alessandro

AU - Cole, Thomas O.

AU - Purks, Julia

AU - Billing, Amy S.

AU - Massey, Ebonie

AU - Wagner, Michael

AU - Wish, Eric D.

AU - Guitart, Xavier

AU - Rea, William

AU - Lam, Sherry

AU - Moreno, Estefanía

AU - Casadó-Anguera, Verònica

AU - Greenblatt, Aaron D.

AU - Jacobson, Arthur E.

AU - Rice, Kenner C.

AU - Casadó, Vicent

AU - Newman, Amy H.

AU - Winkelman, John W.

AU - Michaelides, Michael

AU - Weintraub, Eric

AU - Volkow, Nora D.

AU - Belcher, Annabelle M.

AU - Ferré, Sergi

PY - 2019

Y1 - 2019

N2 - Identifying nonaddictive opioid medications is a high priority in medical science, but μ-opioid receptors (MORs) mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of MORs with galanin Gal1 receptors (Gal1Rs), rendering a profound decrease in the potency of methadone. This finding was explained by the weaker proficiency of methadone in activating the dopaminergic system as compared with morphine and predicted a dissociation of the therapeutic and euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-reports of feeling “high” in methadone-medicated patients. These results suggest that μ-opioid-Gal1R heteromers mediate the dopaminergic effects of opioids. The results further suggest a lower addictive liability of some opioids, such as methadone, due to their selective low potency for the μ-opioid-Gal1R heteromer.

AB - Identifying nonaddictive opioid medications is a high priority in medical science, but μ-opioid receptors (MORs) mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of MORs with galanin Gal1 receptors (Gal1Rs), rendering a profound decrease in the potency of methadone. This finding was explained by the weaker proficiency of methadone in activating the dopaminergic system as compared with morphine and predicted a dissociation of the therapeutic and euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-reports of feeling “high” in methadone-medicated patients. These results suggest that μ-opioid-Gal1R heteromers mediate the dopaminergic effects of opioids. The results further suggest a lower addictive liability of some opioids, such as methadone, due to their selective low potency for the μ-opioid-Gal1R heteromer.

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Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids

Abstract

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