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Biochemistry, Endogenous Opioids

Editor: Forshing Lui Updated: 6/12/2023 7:51:37 PM


Opiates, among the oldest drugs known to humankind, have been used medically for thousands of years for pain relief 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 systems.[1] 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).[2][3] 

Subsequently, a plethora of other endogenous opioid peptides were identified. The endogenous opioid system is vital in regulating various physiologic functions like pain relief (analgesia), euphoria induction, stress resilience, cardiovascular protection, food intake control, etc.[4] Three genetically distinct opioid peptides families are considered classical members of the endogenous opioid system:[5]

  • Endorphins
  • Enkephalins
  • Dynorphin

Issues of Concern

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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.[6][7] Animal studies also show that tolerance may develop due to the cellular changes in the laminae of the dorsal horn of the spinal cord.[8]

Cellular Level

Anatomical Distribution

Different brain areas contain different opioid peptide-producing neurons. Enkephalins-producing neurons are found in multiple brain regions. Enkephalins are involved in the regulation of several biological processes in different organs, including the cardiovascular system, gastrointestinal tract, respiratory system, and pain perception.[9] 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.[10]

Emotional responses are regulated by their action on the limbic system, mainly the amygdala. Other areas with a high concentration of enkephalinergic neurons include the hypothalamus and basal ganglia, particularly globus pallidus. Their respiratory and cardiovascular effects are mediated by their action on the autonomic nuclei of the hypothalamus.[11] In rats, they have been found to stimulate the release of several pituitary hormones such as growth hormone, prolactin, and vasopressin.[12] 

These findings further enhance their neuroendocrine roles. Neurons containing beta-endorphins are predominantly found in the anterior and intermediate lobe of the pituitary and brain stem (the nucleus of tractus solitarius).[13] Most dynorphinergic neurons are found in the posterior lobe of the hypothalamus.[14] Peripherally, opioid peptides are found in the adrenal gland, gastrointestinal tract, heart, pancreas, and many organ tissues.[15][16]

Molecular Level

Endogenous opioids are neurotransmitters or neuromodulators that act by changing the electrical properties of other target neurons, thereby making these neurons difficult to excite.[17] Similar to 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 prepro- and pro-forms which are cleaved sequentially. Based on the cellular biological programs and needs, they are modified by post-translational events, including acetylation, glycosylation, phosphorylation, and methylation. This type of modification is a critical step in the regional regulation of the opioid system because it changes their potencies, pharmacological profile, receptor affinity, or selectivity. They are derived from three gene product proteins, pro-opiomelanocortin (POMC), pro-enkephalin (PENK), and prodynorphin (PDYN) which are precursors for endorphins, enkephalins, and dynorphins respectively.[18] The opioid peptides share a common amino-terminal sequence called the opioid motif, which is Tyr-Gly-Gly-Phe-Met/Leu.[19]

Pro-opiomelanocortin is a polypeptide 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.[20] In addition to their neuromodulatory roles, Beta-endorphins are also secreted into the bloodstream by the pituitary gland (hormone) and have dual neurohormonal functionality.[21]

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 acting on the N-terminal morphine motif. Enkephalinase-A splits the Gly-Phe bond, and enkephalinase-B breaks the Gly-Gly bond. Aminopeptidase N (APN), which splits the 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.[22][23] The third precursor molecule, prodynorphin, is a protein composed of three main leu-enkephalin-containing peptides: dynorphin A, dynorphin B, and neoendorphin. The final form of dynorphin is an area of active research.[24]


The action of endogenous opioids is regulated by their action on the specific opioid receptor. Three major classes of opioid receptors have been identified. Three major categories of opioid receptors have been identified and cloned: mu-opioid receptor (MOR), kappa-opioid receptor (KOR), and delta-opioid receptor (DOR), with differences in affinity and selectivity to endogenous peptides.[25] Opioid receptors are involved in different physiologic functions and effects, including:

  • Pain modulation: This is one of their major effects, and studies have shown that the levels of beta-endorphins rise after oral, gynecologic, and abdominal surgeries.[26][27]
  • Neuroprotection: Research has shown that activation of DOR increases the pro-survival signals and decreases oxidative injury in neurons.[28]
  • Respiratory depression: The degree of respiratory depression depends on the stimulated receptor. MOR produces a significant decrease in the respiratory rate than DOR and KOR.[29]
  • Ionic homeostasis: Activation of DOR decreases the hypoxia-induced ionic imbalance.[30]
  • Constipation: This is due to decreased muscle movement in the gastrointestinal tract.[31]
  • Euphoria
  • Cardioprotection
  • Sedation


The action of opioid compounds is mediated through their 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. In addition to the three classic groups of opioid receptors, the fourth class of receptors has been identified recently, nociception or orphan FQ receptor (NOP/OFQ). Due to the sequence homology, the OFQ receptor does not bind to common opioid ligands but is still considered a part of the opioid family. There is a maximum sequence homology in the cytoplasmic and transmembrane domains and minimum homology in the extracellular domain where the ligand binds.[32]

Opioid receptors belong to a family of 7-transmembrane G-protein-coupled receptors (GPCRs).[33]The main ligands for GPCRs are G-proteins which 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. These events reduce the neuronal firing rate and neurotransmitter release.[34]

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 the 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. Opio-containing interneurons in the dorsal horn terminate where the pain afferents terminate.[35] These interneurons have an inhibitory action on the pain afferents. Activation of postsynaptic opioid receptors hyperpolarises the ascending fibers while presynaptic activation inhibits the release of glutamate and substance P.[17]Together, they reduce the signal transmission in ascending pain pathway. 

The endogenous opioid system also modulates the descending pain suppression pathway by their action on the PAG in the midbrain. The PAG neurons are influenced by the 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.[36]

Clinical Significance

The opioid system is considered one of the most complex neurotransmitter systems in the body that plays a critical role in major biological processes. The use of exogenous opioids for analgesia has limitations due to their undesirable adverse effects, including sedation, respiratory depression, and constipation. However, experiments have shown that drugs that bind to the delta-opioid receptor (DOR) lack respiratory and gastrointestinal adverse effects. So, developing 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 the administration of an opioid antagonist reverses the analgesia induced by acupuncture.[37]

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 demonstrated 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 interesting piece of evidence is the in vivo studies of immunomodulatory activity of enkephalins on rats revealed their dual dose-dependent effect. In other words, high doses of enkephalins 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.[38] Animal studies have shown that opioid receptors are widely involved in neuroprotection, epileptic seizures, and obesity, but their clinical application is yet to be explored.

Placebo-induced pain suppression is another area for clinical research on opioids. Placebo induces the release of endogenous opioids in anticipation of pain relief. Functional MRI (fMRI) response shows that placebo enhances the response in the rostral anterior cingulate gyrus, periaqueductal gray, rostral ventromedial medulla, and hypothalamus.[39] Administration of opioid antagonist naloxone reduces the activity linking endogenous opioids and placebo-induced analgesia in these areas.

A new class of endogenous opioids, endomorphins, has been identified, with the highest affinity and selectively for mu-opioid receptors. Research has found their remarkable role in neuropathic pain, unlike other opioid analgesics.[10] Also, hemorphin is a newly discovered atypical opioid peptide generated by the enzymatic cleavage of hemoglobin. Hemorphins can inhibit angiotensin-converting enzyme (ACE), thus decreasing the blood pressure observed after strenuous physical exercise. However, further studies are necessary to characterize their role in health and disease.[40]



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