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Endogenous opioid system: a promising target for future smoking cessation medications

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Abstract

Background

Nicotine addiction continues to be a health challenge across the world. Despite several approved medications, smokers continue to relapse. Several human and animal studies have evaluated the role of the endogenous opioid system as a potential target for smoking cessation medications.

Methods

In this review, studies that have elucidated the role of the mu (MORs), delta (DORs), and kappa (KORs) opioid receptors in nicotine reward, nicotine withdrawal, and reinstatement of nicotine seeking will be discussed. Additionally, the review will discuss discrepancies in the literature and therapeutic potential of the endogenous opioid system, and suggest studies to address gaps in knowledge with respect to the role of the opioid receptors in nicotine dependence.

Results

Data available till date suggest that blockade of the MORs and DORs decreased the rewarding effects of nicotine, while activation of the MORs and DORs decreased nicotine withdrawal-induced aversive effects. In contrast, activation of the KORs decreased the rewarding effects of nicotine, while blockade of the KORs decreased nicotine withdrawal-induced aversive effects. Interestingly, blockade of the MORs and KORs attenuated reinstatement of nicotine seeking. In humans, MOR antagonists have shown benefits in select subpopulations of smokers and further investigation is required to realize their full therapeutic potential.

Conclusion

Future work must assess the influence of polymorphisms in opioid receptor-linked genes in nicotine dependence, which will help in both identifying individuals vulnerable to nicotine addiction and the development of opioid-based smoking cessation medications. Overall, the endogenous opioid system continues to be a promising target for future smoking cessation medications.

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Abbreviations

AMPA:

Amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate

CPP:

Conditioned place preference

CPA:

Conditioned place version

DAMGO:

[D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin

DORs:

Delta opioid receptors

GNTI:

Guanidinonaltrindole

ICSS:

Intracranial self-stimulation

KORs:

Kappa opioid receptors

MK-801:

(5R,10S)-(−)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cylcohepten-5,10-imine

MORs:

Mu opioid receptors

NAcc:

Nucleus accumbens

NMDA:

N-methyl-D-aspartate

VTA:

Ventral tegmental area

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Acknowledgements

This work was supported by a New Investigator grant from the American Association of Colleges of Pharmacy to Dr. Manoranjan S. D’Souza. This article is dedicated to the memory of Dr. Athina Markou, an excellent researcher and a wonderful mentor, who continues to inspire all of her mentees and the scientific community even though she is no more with us.

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  1. Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH, 45810, USA

    Haval Norman & Manoranjan S. D’Souza

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  1. Haval Norman
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  2. Manoranjan S. D’Souza
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Correspondence to Manoranjan S. D’Souza.

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Norman, H., D’Souza, M.S. Endogenous opioid system: a promising target for future smoking cessation medications. Psychopharmacology 234, 1371–1394 (2017). https://doi.org/10.1007/s00213-017-4582-0

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