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Evolution and challenges of opioids in pain management: Understanding mechanisms and exploring strategies for safer analgesics

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Abstract

Opioids traced back to ancient civilizations, have evolved in their usage for acute and chronic pain treatment. Their interaction with the endogenous opioidergic system modulates pain thresholds, neurological functions, and beyond. The discovery of opioid receptor subtypes (MOP, KOP, DOP, and NOP) revolutionized pharmacology, shedding light on their distinctive roles and signaling pathways. However, despite the efficacy of opioids, complications such as tolerance, addiction, and adverse behavioral effects pose significant challenges. This article explores the mechanisms of opioid activity in cells, emphasizing the role of biased agonism in the analgesic and adverse effects of opioids. We further reviewed strategies to mitigate the side effects, including the development of biased agonists targeting G-proteins, exploration of opioid receptor heterodimers, allosteric activation, and selective targeting of receptor splice variants. Insights into the sodium channel’s role and bitopic modulators also offer new avenues for drug design. The quest to develop safer and more effective analgesics while minimizing adverse effects drives ongoing research. The comprehensive understanding of opioid receptors and innovative strategies offer hope for addressing the opioid crisis and advancing pain management paradigms.

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Abbreviations

AC:

Adenylyl cyclase

ACTH:

Adrenocorticotropin

AQP3:

Aquaporin-3

cAMP:

Cyclic adenosine monophosphate

CNS:

Central nervous system

CPP:

Conditioned place preference

CRH:

Corticotropin-releasing hormone

DHEA:

Dehydroepiandrosterone

DHEAS:

Dehydroepiandrosterone sulfates

DOP:

Delta opioid receptor

DRG:

Dorsal root ganglion

DSt:

Dorsal striatum

GABA:

Gamma-aminobutyric acid

GI:

Gastrointestinal

GlyRα3:

Glycine receptor type α3

GnRH:

Gonadotrophin-releasing hormone

GPCR:

G protein-coupled receptor

GRK:

G-protein receptor kinase

IRP:

Inwardly rectifying potassium

KO:

Knock out

KOP:

Kappa opioid receptor

LC:

Locus coeruleus

LH:

Luteinizing hormone

M3G:

Morphine 3-glucuronide

MDORH:

Mu-delta opioid receptor heterodimer

MOP:

Mu opioid receptor

NAc:

Nucleus accumbens

NAM:

Negative allosteric modulator

NK1:

Neurokinin-1

NMDA:

N-methyl-D-aspartate

NRM:

Nucleus raphe magnus

OE:

Opioid endocrinopathy

OPIAD:

Opioid-induced androgen deficiency

OPRM1:

Opioid receptor mu 1

OUD:

Opioid use disorder

PAG:

Periaqueductal grey

PAM:

Positive allosteric modulator

PKC:

Protein kinase C

TM:

Transmembrane

TRPV1:

Transient receptor potential vanilloid 1

VSCC:

Voltage-sensitive calcium channels

VTA:

Ventral tegmental area

WHO:

World Health Organization

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Acknowledgements

I extend my sincere gratitude to the esteemed faculty members of the Department of Nursing Sciences at Babcock University, whose exceptional mentorship has been instrumental in shaping the content of this publication. Their commitment to fostering critical thinking skills has served as a source of inspiration, contributing significantly to the development of this scholarly work. In addition, I wish to express my heartfelt appreciation to my husband, Mr. Adewale Bakare, whose unwavering support has been a pillar throughout this academic journey. My gratitude extends to my parents, Mr. Alfred Alaba Durojaye and Mrs. Modupe Oluwatoyin Durojaye, for their constant encouragement and support. I am also thankful for the solidarity of my siblings, friends, and colleagues, whose collective encouragement has been invaluable. Lastly, I acknowledge and appreciate the management of The Alpha Assisted Reproductive Klinic for their enduring love and support throughout the years. Their encouragement has played a pivotal role in the realization of my academic pursuits.

Author contributions

TTB: Conceptualization, literature review, writing of first draft, and manuscript editing. HOU: Literature review, validation, and manuscript editing. LNG: Literature review and manuscript editing. SC: Literature review and manuscript editing. JNA: Literature review. AVA: Literature review. SPE: Manuscript editing. CMD: Literature review. GOI: Manuscript editing. AGO: Preparation of figures and manuscript editing. OAD: Conceptualization, preparation of figures, manuscript writing, and editing. All authors have read and approved the manuscript.

Funding

The authors received no funding for this project from any organization.

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Authors and Affiliations

  1. Department of Nursing Sciences, Babcock University, Ilishan-Remo, Ogun State, Nigeria

    Toluwalope Temitope Bakare

  2. Nursing Department, The Alpha Assisted Reproductive Klinic, Ikoyi, Lagos State, Nigeria

    Toluwalope Temitope Bakare

  3. Department of Therapy and Applied Science, Federal College of Dental Technology and Therapy, Enugu, Nigeria

    Henrietta Onyinye Uzoeto

  4. Department of Biological Sciences, Coal City University, Emene, Enugu State, Nigeria

    Henrietta Onyinye Uzoeto, Chizoba Maryann Didiugwu & Glory Omini Ibiang

  5. University of Maryland School of Nursing, 655 W. Lombard St., Baltimore, MD, 21201, USA

    Laywonmen Newon Gonlepa

  6. Department of Biochemistry, University of Nigeria, Nsukka, Enugu State, Nigeria

    Samuel Cosmas

  7. Biochemistry Department, State University of Medical and Applied Sciences, Igbo Eno, Enugu State, Nigeria

    Judith Nnedimkpa Ajima

  8. Department of Chemical Sciences, Coal City University, Emene, Enugu State, Nigeria

    Judith Nnedimkpa Ajima & Olanrewaju Ayodeji Durojaye

  9. Department of Science Laboratory Technology, University of Nigeria, Nsukka, Enugu State, Nigeria

    Amarachukwu Vivian Arazu

  10. Department of Microbiology, University of Nigeria, Nsukka, Enugu State, Nigeria

    Somtochukwu Precious Ezechukwu

  11. School of Earth and Space Sciences, University of Science and Technology of China, Hefei, China

    Abayomi Gaius Osotuyi

  12. MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China

    Olanrewaju Ayodeji Durojaye

  13. School of Life Sciences, Department of Molecular and Cell Biology, University of Science and Technology of China, Hefei, China

    Olanrewaju Ayodeji Durojaye

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  1. Toluwalope Temitope Bakare
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  2. Henrietta Onyinye Uzoeto
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Bakare, T.T., Uzoeto, H.O., Gonlepa, L.N. et al. Evolution and challenges of opioids in pain management: Understanding mechanisms and exploring strategies for safer analgesics. Med Chem Res 33, 563–579 (2024). https://doi.org/10.1007/s00044-024-03207-1

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