The Opioid System Form and Function

Understanding the physiology of the opioid system

transparent person outline with brain

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 as1,2:

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

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

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

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

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

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 complications2,4
  •  Immune dysfunction2
  •  Cardiac distress1,2,4
  •  Reproductive disorders5
  •  Respiratory depression2
COMPONENTS

An extensive network of opioid receptors and ligands interact to modulate signaling pathways1,6

Graphic showing the location of the central nervous system and peripheral areas
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:

Mu (μ) opioid receptors (MORs)2,8
  •  Located in areas of the central nervous system that are involved in pain perception, pleasure, and reward4,6,9
  •  Activation can produce a range of effects, including analgesia, euphoria, and respiratory control2,9
  •  In the periphery, distributed throughout areas including the pancreas, small intestine, and adrenal gland7
Infographic showing mu opioid receptors in the brain
central nervous system
Kappa (k) opioid receptors (KORs)2,8
  •  Found in areas of the central nervous system that are involved in analgesia, stress, and addiction4,6,9
  •  Activation can produce pain relief, as well as dysphoria and other negative effects2,9
  •  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
Kappa brain visualization
central nervous system
Delta (δ) opioid receptors (DORs)2,8
  •  Involved in pain perception4,6,9
  •  May also play a role in analgesia and gastric motility2,9
  •  Nearly identical expression pattern to locations of KOR with the exceptions of the spleen and liver, where DOR is not expressed7
Delta brain visualization
Delta body visualization
Mu (μ) opioid receptors (MORs)2,8
  •  Located in areas of the central nervous system that are involved in pain perception, pleasure, and reward4,6,9
  •  Activation can produce a range of effects, including analgesia, euphoria, and respiratory control2,9
  •  In the periphery, distributed throughout areas including the pancreas, small intestine, and adrenal gland7
Infographic showing mu opioid receptors in the brain
Infographic showing mu opioid receptors in the body
Kappa (k) opioid receptors (KORs)2,8
  •  Found in areas of the central nervous system that are involved in analgesia, stress, and addiction4,8
  •  Activation can produce pain relief, as well as dysphoria and other negative effects2,9
  •  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
Infographic showing kappa opioid receptors in the brain
Infographic showing kappa opioid receptors in the body
Delta (δ) opioid receptors (DORs)2,8
  •  Involved in pain perception8
  •  May also play a role in analgesia and gastric motility2,9
  •  Nearly identical expression pattern to locations of KOR with the exceptions of the spleen and liver, where DOR is not expressed7
Infographic showing delta opioid receptors in the brain
Infographic showing delta opioid receptors in the body
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 receptors11,12

Agonism

arrow down
receptor
agonist
burst

Activation

receptor
cell
agonist
agonist
receptor

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

Antagonism

receptor
agonist
agonist
off

No activation

receptor
cell
agonist
agonist
receptor

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 subtypes10,11

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 them9,11

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

Infographic showing opioid antagonists blocking the action of opioid agonists

References: 1. Shenoy SS, Lui F. Biochemistry, endogenous opioids. In: StatPearls. NCBI Bookshelf. StatPearls Publishing; 2023. Accessed January 3, 2025. https://www.ncbi.nlm.nih.gov/books/NBK532899/ 2. Dhaliwal A, Gupta M. Physiology, opioid receptor. In: StatPearls. NCBI Bookshelf. StatPearls Publishing; 2023. Accessed January 3, 2025. 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 January 3, 2025. 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 January 3, 2025. 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 January 3, 2025. 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 January 3, 2025. 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 January 3, 2025. 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.