The Opioid System System - Form & Function

Understanding the physiology of the
opioid system

The human body's opioid system takes the form of a complex neurotransmitter system that affects major biological functions.¹ An exploration of its form and function is provided here to help educate healthcare professionals on the endogenous opioid system.

Physiologic Functions

The endogenous opioid system is involved in a
range of physiologic functions²

The opioid system, which includes several types of receptors and ligands that are located throughout
the body, affects a wide range of physiological processes, such as^1,2:

Pain modulation³

Activation of the endogenous opioid system plays a role in reducing responses to pain and stress.³

Mood and reward²

Opioid receptors play a role in regulating mood and positive reinforcement.²

Stress response regulation^2,4

Opioid receptors are believed to play a role in stress recovery, including modulating the intensity and duration of the stress response.^2,4

Neuroprotection¹

In neurons, opioid receptors may increase pro-survival signals and reduce oxidative injury.¹

Immune function^2,4

Opioid receptors are present on immune cells, where they have been shown to have immunomodulatory effects on various cell types.^2,4

Cardiovascular function^1,2,4

Opioid receptors are present in cardiac tissue, where they modulate certain functions; for example, short-term effect of decreasing blood pressure and heart rate, and long-term effect of increasing myocardial contraction.^1,2,4

Reproductive function⁵

Endogenous opioids affect many different aspects of male and female reproductive functions, including the release of various sex hormones, follicular growth, ovulation, and spermatogenesis.⁵

Dysregulation

Just as the opioid system affects many different functions in the body, dysregulation of the system may cause an array
of health issues.⁴

Some of these issues include:

Mood changes²
Digestive complications^2,4
Immune dysfunction²
Cardiac distress^1,2,4
Reproductive disorders⁵
Respiratory depression²

Components

An extensive network of opioid receptors and ligands
interact to modulate signaling pathways^1,6

Locations of opioid receptors

Central nervous system

Opioid receptors exist in multiple regions of the brain.^1,4

Peripheral areas

Opioid receptors are also found widely dispersed throughout the body in tissues that are part of the⁷:

Peripheral nervous system
Endocrine system
Respiratory system
Cardiovascular system
Gastrointestinal system
Immune system
Muscular system

There are 3 classic types of opioid receptors⁸:

Kappa

Delta

Mu (μ) opioid receptors (MORs)^2,8

Located in areas of the central nervous system that are involved in pain perception, pleasure, and reward^4,6,9
Activation can produce a range of effects, including analgesia, euphoria, and respiratory control^2,9
In the periphery, distributed throughout areas including the pancreas, small intestine, and adrenal gland⁷

Kappa (κ) opioid receptors (KORs)^2,8

Found in areas of the central nervous system that are involved in analgesia, stress, and addiction^4,8
Activation can produce pain relief, as well as dysphoria and other negative effects^2,9
Unlike MORs, peripheral locations are not limited to the pancreas, small intestine, and adrenal gland but may be found in the lung, heart, kidney, spleen, thymus, skeletal muscle, and liver⁷

Delta (δ) opioid receptors (DORs)^2,8

Involved in pain perception⁸
May also play a role in analgesia and gastric motility^2,9
Nearly identical expression pattern to locations of KOR with the exceptions of the spleen and liver, where DOR is not expressed⁷

There are 3 families of ligands
(also called peptides) specific to
these 3 opioid receptors¹⁰

Endorphins
Enkephalins
Dynorphins

Opioid receptors are distributed throughout the body and have different affinities and selectivity to the different endogenous peptides. Every receptor-ligand interaction has a distinct biochemical activity.¹

Agonists & Antagonists

Agonists and antagonists are 2 types of molecules
that have different effects on receptors^11,12

Agonism

Activation

Agonists bind to specific receptors in the body and activate them, producing a response as a direct result of binding.¹¹

Antagonism

No activation

Antagonists bind to receptors, but rather than activating them, block the action of agonists, thereby inhibiting a response.¹¹

For illustrative purposes only.

Agonists and antagonists can have
different levels of selectivity for
different receptor subtypes^10,11

For example, they may activate or block only one subtype of a receptor, while others may activate or block multiple subtypes.¹¹

Some molecules, called partial agonists, have weak or partial agonist activity, allowing them to act either as a functional agonist or a functional antagonist.¹⁰

Opioid antagonists

Opioid antagonists bind to opioid receptors in the
body but do not activate them^9,11

Like all antagonists, opioid antagonists do not activate receptors. Instead, they block the action of opioid agonists, so the receptors are not activated and a physiological response is inhibited.^9,11

Opioid antagonists are used therapeutically.¹⁰ However, when an opioid agonist is used concomitantly with an opioid antagonist (or any partial agonist or drug with mixed opioid receptor actions), sudden onset of opioid withdrawal symptoms or reduced analgesia may occur.¹⁰

References: 1. Shenoy SS, Lui F. Biochemistry, endogenous opioids. In: StatPearls. NCBI Bookshelf. StatPearls Publishing; 2023. Accessed June 7, 2023. https://www.ncbi.nlm.nih.gov/books/NBK532899/ 2. Dhaliwal A, Gupta M. Physiology, opioid receptor. In: StatPearls. NCBI Bookshelf. StatPearls Publishing; 2023. Accessed June 7, 2023. https://www.ncbi.nlm.nih.gov/books/NBK546642/ 3. Ballester J, Baker AK, Martikainen IK, Koppelmans V, Zubieta JK, Love TM. Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation. Transl Psychiatry. 2022;12(1):20. 4. Cullen JM, Cascella M. Physiology, enkephalin. In: StatPearls. NCBI Bookshelf. StatPearls Publishing; 2023. Accessed June 7, 2023. https://www.ncbi.nlm.nih.gov/books/NBK557764/ 5. Seeber B, Bottcher B, D’Costa E, Wildt L. Opioids and reproduction. Vitam Horm. 2019;111:247-249. 6. Herman TF, Cascella M, Muzio MR. Mu receptors. In: StatPearls. NCBI Bookshelf. StatPearls Publishing; 2023. Accessed June 7, 2023. https://www.ncbi.nlm.nih.gov/books/NBK551554/ 7. Peng J, Sarkar S, Chang SL. Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR. Drug Alcohol Depend. 2012;124(3):223-228. 8. Higginbotham JA, Markovic T, Massaly N, Morón JA. Endogenous opioid systems alterations in pain and opioid use disorder. Front Syst Neurosci. 2022;16:1014768. 9. Theriot J, Sabir S, Azadfard M. Opioid antagonists. In: StatPearls. NCBI Bookshelf. StatPearls Publishing; 2023. Accessed June 7, 2023. https://www.ncbi.nlm.nih.gov/books/NBK537079/ 10. Schumacher MA, Basbaum AI, Naidu RK. Opioid Agonists & Antagonists. In: Katzung BG, Vanderah TW. eds. Basic & Clinical Pharmacology. 15th ed. McGraw Hill; 2021. Accessed June 8, 2023. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988§ionid=250599194 11. Zastrow M. Drug receptors & pharmacodynamics. In: Katzung BG, Vanderah TW, eds. Basic & Clinical Pharmacology. 15th ed. McGraw Hill; 2021. Accessed June 7, 2023. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&ionid=250594122 12. Hackney AC. Hormone and metabolic modulators. In: Doping, Performance Enhancing Drugs, and Hormones in Sport: Mechanisms of Action and Methods of Detection. Elsevier; 2018:77-89.

The Opioid System System - Form & Function

Understanding the physiology of the opioid system

Physiologic Functions

The endogenous opioid system is involved in a range of physiologic functions2

The opioid system, which includes several types of receptors and ligands that are located throughout the body, affects a wide range of physiological processes, such as1,2: