Biochemistry, Endogenous Opioids


Article Author:
Saraswati Satyanarayan Shenoy


Article Editor:
Forshing Lui


Editors In Chief:
Michael Labanowski


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
10/27/2018 12:31:33 PM

Introduction

Opiates, among the oldest drugs known to mankind,  have been used medically for thousands of years for the relief of pain and sedation. They are natural extracts of the poppy plant, Papaver somniferum. In particular, morphine (named after Morpheus the Greek God of dreams) binds to opioid receptors in the central and peripheral nervous system. The search for endogenous ligands for these receptors led to the discovery of two closely related pentapeptides (enkephalins) by Hans Kosterlitz et al. in 1975: methionine-enkephalin (met-enkephalin) and leucine-enkephalin (leu-enkephalin).[1][2] Subsequently, a plethora of other endogenous opioid peptides were identified. The endogenous opioid system plays a vital role in regulating myriad physiologic functions like pain relief (analgesia), euphoria induction, stress resilience, cardiovascular protection, food intake control, and many more. Three genetically distinct opioid peptides families are considered classical members of the endogenous opioid system:

  1. Endorphins
  2. Enkephalins
  3. Dynorphin

Issues of Concern

Opioid Tolerance

Tolerance is a phenomenon in which an increasing dose of the medication is required to produce the same pharmacologic effect. The body develops tolerance after repeated administration, and higher doses of opioids are required to maintain the same level of analgesia. Tolerance develops quickly to sedation, respiratory depression, analgesia, and gastrointestinal distress. However, there is minimal tolerance to constipation and miosis. Tolerance develops by various mechanisms such as desensitization, downregulation, receptor internalization, and mu/delta heterodimer formation. Animal studies also show that tolerance may develop due to the cellular changes in the laminae of the dorsal horn of the spinal cord.

Cellular

Anatomical Distribution

Different brain areas contain different opioid peptide-producing neurons. Neurons producing enkephalins are spread out and are found in different brain regions. Enkephalins are involved in several biological processes (cardiovascular system, gastrointestinal functions, respiration, pain perception). Enkephalinergic neurons are present in Lamina I, II (substantia gelatinosa), and V of the spinal cord and in the periaqueductal gray (PAG) through which they mediate pain perception.[3] Emotional responses are regulated by their action on the limbic system mainly amygdala. Other areas of high concentration include hypothalamus and basal ganglia particularly globus pallidus. The respiratory and cardiovascular function is mediated by their action on the autonomic nuclei of the hypothalamus. In rats, they have been found to stimulate the release of several pituitary hormones, in particular, growth hormone, prolactin, and vasopressin. This points towards their neuroendocrine role.

Neurons containing beta-endorphins are predominantly found in the anterior and intermediate lobe of the pituitary and brain stem (the nucleus of tractus solitarius).

The majority of dynorphinergic neurons are found in the posterior lobe of the hypothalamus. Peripherally, opioid peptides are found in the adrenal gland, gastrointestinal tract, heart, pancreas, and many organ tissues.

Molecular

Endogenous opioids are neurotransmitters or neuromodulators that act by changing the electrical properties of other target neurons, thereby making these neurons difficult to excite. Like other small peptide molecules, endogenous opioids are synthesized as a part of a larger precursor molecule. However, unlike other peptides, opioid peptides have a number of different precursors. Each opioid peptide has a pre-pro and a pro form which cleaves the signal peptide. They are then modified by post-translational events namely acetylation, glycosylation, phosphorylation, and methylation based on the biological program of the cell. These changes result in different potencies, pharmacological profile, receptor affinity, or selectivity and is a critical step in the regulation of the opioid system in a particular region. They are derived from three gene product proteins, namely pro-opiomelanocortin (POMC), pro-enkephalin (PENK) and prodynorphin (PDYN) which are precursors for endorphins, enkephalins, and dynorphins respectively. The opioid peptides share a common amino-terminal sequence called, the opioid motif which is: Tyr-Gly-Gly-Phe- (Met/Leu)

Pro-opiomelanocortin is a polypeptide that is cleaved by the enzyme peptidase into adrenocorticotropin-releasing hormone (ACTH) and beta-Lipotropin (beta-LPH) containing 93 amino acids. Beta-LPH is further cleaved to yield alpha-melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin (beta-endorphin), a polypeptide containing 31 amino acids. The sequence is Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu. Beta-endorphins are also secreted into the bloodstream by the pituitary gland (hormone) in addition to being neuromodulators, i.e., they express dual functionality.

Pro-enkephalin is a seven-peptide-containing structure, first identified in the adrenal medulla. Each molecule of pro-enkephalin contains four met-enkephalins, one leu-enkephalin, one octapeptide, and one heptapeptide. Enkephalins have a short half-life both in vivo and in vitro. They are metabolized primarily by two peptidases: enkephalinase-A, which splits the Gly-Phe bond, and enkephalinase-B, which splits the Gly-Gly bond. Aminopeptidase N (APN), which splits Tyr-Gly bond, also contributes to its catabolism. Recent studies have developed a mixed peptidase inhibitor, kelatorphan, that completely inhibits the metabolism of exogenous met-enkephalin thereby reducing the intracerebroventricular analgesic dose in mice.[4][5]

The third precursor molecule prodynorphin is a protein that contains three main leu-enkephalin containing peptides: dynorphin A, dynorphin B, and neoendorphin. The final forms of dynorphin is an area of active research.[6]

Function

The action of endogenous opioids is regulated by their action on the specific opioid receptor. Opioid receptors are involved in different physiologic functions. Following are the effects produced:

  • Pain modulation: This is one of the major effects. Studies have shown that the levels of beta-endorphins rise after oral, gynecologic, and abdominal surgeries.
  • Neuroprotection: Studies explain that activation of DOR increase the pro-survival signals, decrease the oxidative injury thereby showing a role in neuroprotection.
  • Respiratory depression: The degree of respiratory depression depends on the receptor-stimulated. MOR produces a significant decrease in the respiratory rate than DOR and KOR.
  • Ionic homeostasis: Activation of DOR decreases the hypoxia-induced ionic imbalance.
  • Constipation: This is due to a decrease in the movement of the muscles of the gastrointestinal tract.
  • Euphoria
  • Cardioprotection
  • Sedation

Mechanism

The action of opioid compounds is mediated through its action on opioid peptide receptors (OPR). Opioid receptors exist throughout the body, but their expression and distribution vary significantly among different organs. An opioid peptide can interact with more than one type of opioid receptor. The receptor-ligand binding engenders a series of biochemical events and brings about various effects. Three major categories of opioid receptors have been identified and cloned: mu-opioid receptor (MOR), kappa-opioid receptor (KOR), and delta-opioid receptor (DOR). A fourth class of receptor has been identified recently, nociception or orphan FQ receptor (NOP/OFQ). The OFQ receptor does not bind to classic opioid ligands but is still considered a part of the opioid family due to the sequence homology. There is a maximum sequence homology in the cytoplasmic and transmembrane domains and minimum homology in the extracellular domain where the ligand binds.

Opioid receptors belong to a family of 7-transmembrane G-protein-coupled receptors. G-proteins are made of three subunits: alpha, beta, and gamma. When a classical opioid agonist binds to its receptor, it results in the inhibition of adenylyl cyclase, which intern reduces intracellular cAMP levels (cyclic-AMP). This leads to increased potassium conductance out of the cell, causing hyperpolarization of the neurons and decreased calcium conductance. Because of this, the neuronal firing rate and neurotransmitter release are reduced.[7]

Opioid-Mediated Pain Suppression

Opioids mediate both ascending and descending pain pathways. The primary afferent pain fibers are the thinly myelinated A-delta fibers and the unmyelinated C fibers. Stimulation of A-delta fibers releases glutamate, which is responsible for fast pain. Stimulation of C fibers leads to release of glutamate and substance P, responsible for slow pain. These afferents reach the dorsal horn of the spinal cord where they synapse with the neurons of the ascending spinothalamic tract. There are opioid-containing interneurons in the dorsal horn that terminate where the pain afferents terminate. These interneurons have an inhibitory action on the pain afferents. Activation of postsynaptic opioid receptors hyperpolarises the ascending fibers while presynaptic activation inhibits release of glutamate and substance P. Together, they reduce the ascending pain transmission.

The endogenous opioid system also modulates the descending pain suppression pathway by their action on the periaqueductal gray (PAG) in the midbrain. The PAG neurons are under the influence of inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Opioids inhibit the release of GABA, thus activating the PAG. The neurons of the PAG then activate serotonergic neurons in the nucleus raphe Magnus and noradrenergic neurons in the rostral ventromedial medulla. These neurotransmitters stimulate the enkephalinergic interneurons in the spinal cord, thus inhibiting pain perception.

Clinical Significance

The opioid system is believed to be one of the most complex neurotransmitter systems in the body that plays a critical role in major biological processes in the body. The use of exogenous opioids for analgesia have limitations due to their undesirable adverse effects which include sedation, respiratory depression, and constipation. However, experiments have found that drugs that bind to the delta-opioid receptor (DOR) lack respiratory and gastrointestinal adverse effects. So, development of DOR specific drugs will prove to be a clinical advantage. Research suggests that acupuncture produces analgesia by the release of endogenous opioids. This is supported by the finding that administration of an opioid antagonist reverses the analgesia induced by acupuncture.[8]

Another notable finding is the correlation between alcohol consumption and endogenous opioids. Alcohol induces the activation of the endogenous opioid system. Clinical trials on outpatient alcoholics have shown that administration of opioid antagonist naltrexone decreased the average number of drinking days per week, the desire to drink, and the alcohol-induced high. Another important study is the in vivo studies of immunomodulator activity of enkephalins on rats which revealed a dual dose-dependent effect, i.e., high doses inhibit while low doses enhance the immune response. Recent investigations suggest that enkephalins act as modulators of cardiac function and play a vital role in aging, ischaemic preconditioning, heart failure, and hypertension.[9] Studies on animal models have shown that opioid receptors are widely involved in neuroprotection, epileptic seizures, and obesity, but its clinical significance is undergoing research.

An important hypothesis is that of placebo-induced pain suppression. Placebo induces the release of endogenous opioids in anticipation of pain relief. Functional MRI (fMRI) response shows placebo-enhanced response in the rostral anterior cingulate gyrus, periaqueductal gray, rostral ventromedial medulla, and hypothalamus.[10] Administration of opioid antagonist naloxone, reduces the activity in these areas, thus showing the link between endogenous opioids and placebo-induced analgesia.

A new class of endogenous peptides, endomorphins, has been identified which have the highest affinity and selectively for mu-opioid receptor. Evidence has revealed their remarkable role in neuropathic pain, unlike other known opioid analgesics.[3] Also, a novel discovery of an atypical opioid peptide is hemorphin. These are endogenous peptides generated by enzymatic cleavage of hemoglobin. Hemorphins can inhibit angiotensin-converting enzyme (ACE), thus decreasing the blood pressure observed after strenuous physical exercise. However, further studies have to be done to draw a firm conclusion.[11]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Biochemistry, Endogenous Opioids - Questions

Take a quiz of the questions on this article.

Take Quiz
Endogenous opioids are released by which area within the brain?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 43-year-old man was brought to the emergency department by his relatives as he was not responding. On examination, his blood pressure was 100/60 mmHg, respiratory rate was 7/min. His pupils were constricted, and he had an altered mental status. Relatives revealed that he was on morphine for severe cancer-related pain. There were empty syringes beside his bed. Arterial blood gas analysis revealed a raised partial pressure of carbon dioxide. He was suspected to have opioid intoxication. How does morphine act postsynaptically to control his pain?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is characteristic about enkephalinergic neurons? (A) Most have long axons. (B) They carry pain signals from the periphery to the spinal cord. (C) They are present in lamina II and V of the spinal cord. (D) Most have local actions indicating short axons.



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Endogenous opioids are known to modulate pain perception through central and peripheral ways. By which of the following mechanisms do they inhibit pain centrally?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 65-year-old old man presents with symptoms of severe abdominal pain, loss of appetite, diarrhea, and weight loss over past couple of months. He also complains of painful swollen skin lesions. Laboratory investigations showed raised bilirubin, raised alkaline phosphate and very high blood glucose. He was started on opioids for controlling his pain. In which of the following locations do opioids act to suppress the affective component of pain?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 40-year-old man is taking opioids for over six months. Which of the following effects is seen in him?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Biochemistry, Endogenous Opioids - References

References

Snyder SH,Pasternak GW, Historical review: Opioid receptors. Trends in pharmacological sciences. 2003 Apr     [PubMed]
Lewis RV,Stern AS, Biosynthesis of the enkephalins and enkephalin-containing polypeptides. Annual review of pharmacology and toxicology. 1983     [PubMed]
Imura H,Nakai Y,Nakao K,Oki S,Tanaka I,Jingami H,Yoshimasa T,Tsukada T,Ikeda Y,Suda M,Sakamoto M, Biosynthesis and distribution of opioid peptides. Journal of endocrinological investigation. 1983 Apr     [PubMed]
Fournie-Zaluski MC,Chaillet P,Bouboutou R,Coulaud A,Cherot P,Waksman G,Costentin J,Roques BP, Analgesic effects of kelatorphan, a new highly potent inhibitor of multiple enkephalin degrading enzymes. European journal of pharmacology. 1984 Jul 20     [PubMed]
Williams J, Basic Opioid Pharmacology. Reviews in pain. 2008 Mar     [PubMed]
Holden JE,Jeong Y,Forrest JM, The endogenous opioid system and clinical pain management. AACN clinical issues. 2005 Jul-Sep     [PubMed]
He LF, Involvement of endogenous opioid peptides in acupuncture analgesia. Pain. 1987 Oct     [PubMed]
van den Brink OW,Delbridge LM,Rosenfeldt FL,Penny D,Esmore DS,Quick D,Kaye DM,Pepe S, Endogenous cardiac opioids: enkephalins in adaptation and protection of the heart. Heart, lung     [PubMed]
Bingel U,Lorenz J,Schoell E,Weiller C,Büchel C, Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain. 2006 Jan     [PubMed]
Nyberg F,Sanderson K,Glämsta EL, The hemorphins: a new class of opioid peptides derived from the blood protein hemoglobin. Biopolymers. 1997     [PubMed]
Hughes J,Smith TW,Kosterlitz HW,Fothergill LA,Morgan BA,Morris HR, Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature. 1975 Dec 18     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Neurology-Neurodevelopmental. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Neurology-Neurodevelopmental, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Neurology-Neurodevelopmental, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Neurology-Neurodevelopmental. When it is time for the Neurology-Neurodevelopmental board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Neurology-Neurodevelopmental.