Fentanyl is an opiate painkiller, meaning that it acts on our endogenous opioid receptors to help relieve pain.
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The endogenous opioid system is activated in a similar way to when you're in a state of elation or after you've had some really good exercise.
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Exactly how causes the release of endogenous opioid peptides remains uncertain.
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Neoendorphins are a group of endogenous opioid peptides derived from the proteolytic cleavage of prodynorphin. They include α-neoendorphin and β-neoendorphin.
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After graduating from UNC in 2004, Wassum continued on to pursue her graduate studies at the University of California, Los Angeles. At UCLA, Wassum worked under the mentorship of Dr. Bernard Balleine and Dr. Nigel Maidment studying the role of endogenous opioids in reward learning. Wassum found that the endogenous opioid system is necessary for goal-directed learning and inhibition of endogenous opioid signalling leads to enhanced habit-learning. Her first author paper in the journal Neuroscience highlighted the critical role played by endogenous opioids in learning.
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Sensitization can be initiated by inflammatory prostaglandins or leukotrienes and are therefore the targets of nonsteroidal anti-inflammatory (NSAIDs) which block key enzymes in their synthesis. Additionally, opioid drugs suppress nociceptions by binding to endogenous opioid receptors.
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Exorphins are exogenous opioid peptides, distinguished from endorphins (or endogenous opioid peptides). Exorphins include opioid food peptides like Gluten exorphin and microbial opioid peptides and any other opioid peptide foreign to a host that have metabolic efficacy for that host.
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Dense-core vesicle storage is characteristic of opioid peptides storage. The first clues to the functionality of dynorphins came from Goldstein et al. in their work with opioid peptides. The group discovered an endogenous opioid peptide in the porcine pituitary that proved difficult to isolate.
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Most genetic studies in addiction research focus on the genetic determinants of diagnostic phenotypes such as alcohol use disorder. However, because the causes of alcohol use disorder are so numerous and varied, researchers have turned their attention to endophenotypes, or distinct, genetically-linked phenotypes associated with a broad disorder. Endophenotypes are especially useful in addictions research because they are more closely linked to genetic variations than the broad disorder. Therefore, investigators have explored the effects of genetic variation in the endogenous opioid system and the GABAergic system on SR. Alcohol activates endogenous opioid receptors, potentiating dopamine release which increases the rewarding effects of alcohol.
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Proenkephalin (PENK), formerly known as proenkephalin A (since proenkephalin B was renamed prodynorphin), is an endogenous opioid polypeptide hormone which, via proteolyic cleavage, produces the enkephalin peptides [Met]enkephalin, and to a lesser extent, [Leu]enkephalin. Upon cleavage, each proenkephalin peptide results in the generation of four copies of [Met]enkephalin, two extended copies of [Met]enkephalin, and one copy of [Leu]enkephalin. Contrarily, [Leu]enkephalin] is predominantly synthesized from prodynorphin, which produces three copies of it per cleavage, and no copies of [Met]enkephalin. Other endogenous opioid peptides produced by proenkephalin include adrenorphin, amidorphin, BAM-18, BAM-20P, BAM-22P, peptide B, peptide E, and peptide F.
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Ream Al-Hasani is a British neuroscientist and pharmacologist as well as an Assistant Professor of Anesthesiology at Washington University in St. Louis, Missouri. Al-Hasani studies the endogenous opioid system to understand how to target it therapeutically to treat addiction, affective disorders, and chronic pain.
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Sigma (σ) receptors were once considered to be opioid receptors due to the antitussive actions of many opioid drugs' being mediated via σ receptors, and the first selective σ agonists being derivatives of opioid drugs (e.g., allylnormetazocine). However, σ receptors were found to not be activated by endogenous opioid peptides, and are quite different from the other opioid receptors in both function and gene sequence, so they are now not usually classified with the opioid receptors. The existence of further opioid receptors (or receptor subtypes) has also been suggested because of pharmacological evidence of actions produced by endogenous opioid peptides, but shown not to be mediated through any of the four known opioid receptor subtypes.
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Leumorphin, also known as dynorphin B1–29, is a naturally occurring endogenous opioid peptide. Derived as a proteolytic cleavage product of residues 226-254 of prodynorphin (preproenkephalin B), leumorphin is a nonacosapeptide (29 amino acids in length) and has the sequence Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln- Phe-Lys-Val-Val-Thr-Arg-Ser-Gln-Glu-Asp-Pro-Asn-Ala-Tyr-Ser-Gly-Glu-Leu-Phe- Asp-Ala. It can be further reduced to dynorphin B (dynorphin B-13) and dynorphin B-14 by pitrilysin metallopeptidase 1 (formerly referred to as "dynorphin-converting enzyme"), an enzyme of the endopeptidase family. Leumorphin behaves as a potent and selective κ-opioid receptor agonist, similarly to other endogenous opioid peptide derivatives of prodynorphin.
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Dynorphin B, also known as rimorphin, is a form of dynorphin and an endogenous opioid peptide with the amino acid sequence Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln- Phe-Lys-Val-Val-Thr. Dynorphin B is generated as a proteolyic cleavage product of leumorphin, which in turn is a cleavage product of preproenkephalin B (prodynorphin).
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Cyprenorphine also has been shown to suppress the intake of sweet solution but doesn't suppress the increase in food consumption that's produced by the alpha-2-adrenoceptor antagonist idazoxan. Idazoxan may lead to the release of endogenous opioid peptides and increase food intake, this effect is attenuated by (-)-naloxone but not by the mu/delta-antagonist cyprenorphine.
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Psychoactive drugs are often prescribed to manage pain. The subjective experience of pain is primarily regulated by endogenous opioid peptides. Thus, pain can often be managed using psychoactives that operate on this neurotransmitter system, also known as opioid receptor agonists. This class of drugs can be highly addictive, and includes opiate narcotics, like morphine and codeine.
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Endorphins (contracted from " _endo_ genous mo _rphin_ e") are endogenous opioid neuropeptides and peptide hormones in humans and other animals. They are produced and stored in the pituitary gland. The classification of molecules as endorphins is based on their pharmacological activity, as opposed to a specific chemical formulation. The endorphin class consists of α-endorphin, β-endorphin, and γ-endorphin.
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An enkephalinase inhibitor is a type of enzyme inhibitor which inhibits one or more members of the enkephalinase class of enzymes that break down the endogenous enkephalin opioid peptides. Examples include racecadotril, ubenimex (bestatin), RB-101, and D-phenylalanine, as well as the endogenous opioid peptides opiorphin and spinorphin. Analgesic, anticraving, antidepressant, anxiolytic, and antidiarrheal effects are common properties of enkephalinase inhibitors.
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Stein C, Schäfer M, Machelska H (2003) Attacking pain at its source: new perspectives on opioids. Nature Med;9(8):1003-1008. . Since inflammatory pain is blunted by endogenous opioid peptides activating such peripheral opioid receptors,Busch-Dienstfertig M, Stein C (2010) Opioid receptors and opioid peptide-producing leukocytes in inflammatory pain-basic and therapeutic aspects. Brain Behav. Immun. 24(5):683-694. .
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The muscle relaxant properties of nitrazepam are produced via inhibition of polysynaptic pathways in the spinal cord of decerebrate cats. It is a full agonist of the benzodiazepine receptor. The endogenous opioid system may play a role in some of the pharmacological properties of nitrazepam in rats. Nitrazepam causes a decrease in the cerebral contents of the amino acids glycine and alanine in the mouse brain.
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Opioid peptides are known to play a role in emotion and motivation. The content of β-endorphin (β-EP), an endogenous opioid peptide, has been found to decrease (in varying amounts/brain region) post ovariectomy in female rats within the hypothalamus, hippocampus, and pituitary gland. Such a change in β-EP levels could be the cause of mood swings, behavioral disturbances, and hot flashes in post menopausal women.
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The nucleus raphes dorsalis has also been implicated in naloxone-induced morphine withdrawal. It is known that endogenous opioid receptors exist on the nucleus raphes dorsalis, and that it is a focal point as an ascending and descending regulator. Pourshanazari et al. showed in their 2000 paper that electrical stimulation of the nucleus raphes dorsalis can partially alleviate morphine withdrawal symptoms via electrical stimulation of the raphe nucleus in question.
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The μ-opioid receptor also binds endogenous opioid peptides such as β-endorphin, Leu-enkephalin, and Met-enkephalin. Repeated use of heroin results in a number of physiological changes, including an increase in the production of μ-opioid receptors (upregulation). These physiological alterations lead to tolerance and dependence, so that stopping heroin use results in uncomfortable symptoms including pain, anxiety, muscle spasms, and insomnia called the opioid withdrawal syndrome.
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Met-enkephalin, also known as metenkefalin (INN), sometimes referred to as opioid growth factor (OGF), is a naturally occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkephalin, the other being leu-enkephalin. The enkephalins are considered to be the primary endogenous ligands of the δ-opioid receptor, due to their high potency and selectivity for the site over the other endogenous opioids.
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Continuous exercise can produce a transient state of euphoria – a positively-valenced affective state involving the experience of pleasure and feelings of profound contentment, elation, and well-being – which is colloquially known as a "runner's high" in distance running or a "rower's high" in rowing. Current medical reviews indicate that several endogenous euphoriants are responsible for producing exercise-related euphoria, specifically phenethylamine (an endogenous psychostimulant), (an endogenous opioid), and anandamide (an endogenous cannabinoid).
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The researchers began investigating why some alcoholics respond well to Naltrexone while others do not. Their work led to the discovery of genes that determine the extent of pleasure one feels when drinking alcohol.Neuropsychopharmacology, 2003 Individuals with a particular genetic variant have a sensitive endogenous opioid system that is activated by alcohol, thereby producing stimulation and euphoria. Naltrexone blocks this form of alcohol reward, so the medication is particularly effective for these individuals.
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Dynorphin A is a dynorphin, an endogenous opioid peptide with the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys. Dynorphin A1–8 is a truncated form of dynorphin A with the amino acid sequence: Tyr-Gly-Gly- Phe-Leu-Arg-Arg-Ile. Dynorphin A1–8 is an agonist at the mu-, kappa-, and delta-opioid receptors; it has the highest binding affinity for the kappa- opioid receptor.
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Hemorphins are a class of naturally occurring, endogenous opioid peptides which are found in the bloodstream, and are derived from the β-chain of hemoglobin. They have antinociceptive effects via activation of the opioid receptors, and some may also play a role in blood pressure through inhibition of the angiotensin-converting enzyme (ACE), as well as cause an elevation of endogenous enkephalin levels. Some examples of hemorphins include hemorphin-4, spinorphin, and valorphin.
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Endogenous depression (melancholia) is an atypical sub-class of the mood disorder, major depressive disorder (clinical depression). It could be caused by genetic and biological factors. Endogenous depression occurs due to the presence of an internal (cognitive, biological) stressor instead of an external (social, environmental) stressor. Endogenous depression includes patients with treatment-resistant, non-psychotic, major depressive disorder, characterized by abnormal behavior of the endogenous opioid system but not the monoaminergic system.
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Past the optimum point for extraction, various processes in the plant produce codeine, thebaine, and in some cases negligible amounts of hydromorphone, dihydromorphine, dihydrocodeine, tetrahydro-thebaine, and hydrocodone (these compounds are rather synthesized from thebaine and oripavine). In the brain of mammals, morphine is detectable in trace steady-state concentrations. The human body also produces endorphins, which are chemically related endogenous opioid peptides that function as neuropeptides and have similar effects to morphine.
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Permanent brain damage may occur due to cerebral hypoxia or opioid-induced neurotoxicity. Opioids inhibit the medulla's chemoreceptors through the mu and delta receptors. Opioids bind to receptors that are part of the endogenous opioid system as well as other central nervous neurotransmitter systems, binding to excitatory neurotransmitters like dopamine or glutamate, or inhibitory neurotransmitters like GABA. The main excitatory chemoreceptor, glutamate, and main inhibitory chemoreceptor, GABA, are the main neurotransmitters that control respiration.
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The blockade of opioid receptors is the basis behind naltrexone's action in the management of opioid dependence--it reversibly blocks or attenuates the effects of opioids. Its mechanism of action in alcohol dependence is generated via κ-opioid receptor antagonism, which blocks the actions of the endogenous opioid peptide dynorphin. Dynorphin typically instates drug-seeking behavior when it binds to the κ-opioid receptor, as well as decreasing dopaminergic signalling in the nucleus accumbens.
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As the doses used throughout the literature vary, it is difficult to form a conclusion regarding the benefit of naloxone in this setting. The mechanism for naloxone's proposed benefit in clonidine overdose is unclear, but it has been suggested that endogenous opioid receptors mediate the sympathetic nervous system in the brain and elsewhere in the body. Some poison control centers recommend naloxone in the setting of clonidine overdose, including intravenous bolus doses of up to 10 mg naloxone.
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Estradiol influences cognitive function, specifically by enhancing learning and memory in a dose-sensitive manner. Too much estrogen can have negative effects by weakening performance of learned tasks as well as hindering performance of memory tasks; this can result in females exhibiting poorer performance of such tasks when compared to males. Ovariectomies, surgeries inducing menopause, or natural menopause cause fluctuating and decreased estrogen levels in women. This in turn can "attenuate the effects" of endogenous opioid peptides.
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Leu-enkephalin is an endogenous opioid peptide neurotransmitter with the amino acid sequence Tyr-Gly-Gly-Phe-Leu that is found naturally in the brains of many animals, including humans. It is one of the two forms of enkephalin; the other is met-enkephalin. The tyrosine residue at position 1 is thought to be analogous to the 3-hydroxyl group on morphine. Leu-enkephalin has agonistic actions at both the μ- and δ-opioid receptors, with significantly greater preference for the latter.
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Runners can experience a euphoric state often called a "runner's high". Continuous physical exercise, particularly aerobic exercise, can induce a state of euphoria; for example, distance running is often associated with a "runner's high", which is a pronounced state of exercise-induced euphoria. Exercise is known to affect dopamine signaling in the nucleus accumbens, producing euphoria as a result, through increased biosynthesis of three particular neurochemicals: anandamide (an endocannabinoid), β-endorphin (an endogenous opioid), and phenethylamine (a trace amine and amphetamine analog).
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The analgesic effects of are linked to the interaction between the endogenous opioid system and the descending noradrenergic system. When animals are given morphine chronically, they develop tolerance to its pain-killing effects, and this also renders the animals tolerant to the analgesic effects of . Administration of antibodies that bind and block the activity of some endogenous opioids (not β-endorphin) also block the antinociceptive effects of . Drugs that inhibit the breakdown of endogenous opioids also potentiate the antinociceptive effects of .
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Hemorphin-4 is an endogenous opioid peptide of the hemorphin family which possesses antinociceptive properties and is derived from the β-chain of hemoglobin in the bloodstream. It is a tetrapeptide with the amino acid sequence Tyr-Pro-Trp-Thr. Hemorphin-4 has affinities for the μ-, δ-, and κ-opioid receptors that are in the same range as the structurally related β-casomorphins, although affinity to the κ-opioid receptor is markedly higher in comparison. It acts as an agonist at these sites.
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The exact pre-propeptide precursors of endomorphins have not been identified. Because the precursors have never been identified and the mechanisms by which the endomorphins are produced have never been clarified, the status of endomorphins as endogenous opioid ligands has to be considered tentative. Opioid receptors belong to the G protein-coupled receptor family and include μ, κ, δ, and nociceptinorphanin-FQ receptors. While activation of opiate receptors initiates a diverse array of responses, opiates typically serve as depressants, and are widely used and developed as analgesics.
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Big dynorphin is an endogenous opioid peptide of the dynorphin family that is composed of both dynorphin A and dynorphin B. Big dynorphin has the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln- Lys-Arg-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr. It has nociceptive and anxiolytic-like properties, as well as effects on memory in mice. Big dynorphin is a principal endogenous agonist at the human kappa- opioid receptor.
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During a frisson, a sensation of chills or tingling is felt on the skin of the lower back, shoulders, neck, and/or arms. The sensation of chills is sometimes experienced as a series of 'waves' moving up the back in rapid succession and commonly described as "shivers up the spine". Hair follicles may also undergo piloerection. It has been shown that some experiencing musical frisson report reduced excitement when under administration of naloxone (an opioid receptor antagonist), suggesting musical frisson gives rise to endogenous opioid peptides similar to other pleasurable experiences.
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It consists of collecting positive and neutral messages from 6 loved ones of a participant, and presenting them to the participant in the laboratory. Feelings of connection and neural activity in response to this task have been found to rely on endogenous opioid activity. Closeness-generating procedure Arthur Aron at the State University of New York at Stony Brook and collaborators designed a series of questions designed to generate interpersonal closeness between two individuals who have never met. It consists of 36 questions that subject pairs ask each other over a 45-minute period.
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They found that as drug use escalates, so does the presence of CRF in human cerebrospinal fluid. In rat models, the separate use of CRF inhibitors and CRF receptor antagonists both decreased self-administration of the drug of study. Other studies in this review showed dysregulation of other neuropeptides that affect the HPA axis, including enkephalin which is an endogenous opioid peptide that regulates pain. It also appears that µ-opioid receptors, which enkephalin acts upon, is influential in the reward system and can regulate the expression of stress hormones.
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For example, nonpsychotropic cannabinoids can be used as a very effective anti-inflammatory. The affinity of cannabinoids to bind to either receptor is about the same, with only a slight increase observed with the plant-derived compound CBD binding to CB2 receptors more frequently. Cannabinoids likely have a role in the brain's control of movement and memory, as well as natural pain modulation. It is clear that cannabinoids can affect pain transmission and, specifically, that cannabinoids interact with the brain's endogenous opioid system and may affect dopamine transmission.
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Endomorphin-2 (EM-2) is an endogenous opioid peptide and one of the two endomorphins. It has the amino acid sequence Tyr-Pro-Phe-Phe-NH2. It is a high affinity, highly selective agonist of the μ-opioid receptor, and along with endomorphin-1 (EM-1), has been proposed to be the actual endogenous ligand of this receptor (that is, rather than the endorphins). Like EM-1, EM-2 produces analgesia in animals, but whereas EM-1 is more prevalent in the brain, EM-2 is more prevalent in the spinal cord.
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Beta-Endorphin or β-Endorphin, is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin. The amino acid 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 (31 amino acids).DBGET The first 16 amino acids are identical to α-endorphin.
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RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research. RB-101 is a prodrug which acts by splitting at the disulfide bond once inside the brain, to form two selective enzyme inhibitors and blocking both types of the zinc-metallopeptidase enkephalinase enzymes. This inhibits the breakdown of the endogenous opioid peptides known as enkephalins. These two enzymes, aminopeptidase N (APN) and neutral endopeptidase 24.11 (NEP), are responsible for the breakdown of both kinds of enkephalin naturally found in the body, and so RB-101 causes a buildup of both Met-enkephalin and Leu-enkephalin.
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Valorphin, also known as VV-hemorphin-5, is a naturally occurring, endogenous opioid heptapeptide of the hemorphin family with the amino acid sequence H-Val-Val-Tyr-Pro-Trp-Thr-Gln-OH. It is produced in the body via proteolyic cleavage of residues 33-39 of the β-chain of hemoglobin. Valorphin binds preferentially to the μ-opioid receptor and produces effects such as analgesia and self-administration in animals. It also possesses cytotoxic and antiproliferative properties against tumor cells, the mediation of which, because they are reversed by naloxone, appears to be dependent on the opioid receptors.
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Placebo analgesia occurs when the administration of placebos leads to pain relief. Because placebos by definition lack active ingredients, the effect of placebo analgesia is considered to result from the patient's belief that they are receiving an analgesic drug or other medical intervention. It has been shown that, in some cases, the endogenous opioid system is critical for mediating placebo analgesia, as evidenced by the ability of such analgesia to be reduced by the opioid antagonist naloxone. However, it is also possible for placebo analgesia to be mediated by non-opioid mechanisms, in which case it would not be affected by naloxone.
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Endomorphin-1 (EM-1) (amino acid sequence Tyr-Pro-Trp-Phe-NH2) is an endogenous opioid peptide and one of the two endomorphins. It is a high affinity, highly selective agonist of the μ-opioid receptor, and along with endomorphin-2 (EM-2), has been proposed to be the actual endogenous ligand of the μ-receptor. EM-1 produces analgesia in animals and is equipotent with morphine in this regard. The gene encoding for EM-1 has not yet been identified, and it has been suggested that endomorphins could be synthesized by an enzymatic, non-ribosomal mechanism.
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AM-1241 (1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole) is a chemical from the aminoalkylindole family that acts as a potent and selective agonist for the cannabinoid receptor CB2, with a Ki of 3.4 nM at CB2 and 80 times selectivity over the related CB1 receptor. It has analgesic effects in animal studies, particularly against "atypical" pain such as hyperalgesia and allodynia. This is thought to be mediated through CB2-mediated peripheral release of endogenous opioid peptides, as well as direct activation of the TRPA1 channel. It has also shown efficacy in the treatment of amyotrophic lateral sclerosis in animal models.
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Animal studies suggest that RB-101 is also likely to be useful in relieving the symptoms of acute opioid withdrawal and in the management of opioid dependence. A significant advantage of inhibiting the breakdown of endogenous opioid peptides rather than stimulating opioid receptors with exogenous drugs is that the levels of opioid peptides are only increased slightly from natural levels, thus avoiding overstimulation and upregulation of the opioid receptors. This means that even when RB-101 is used in high doses for extended periods of time, there is no development of dependence on the drug or tolerance to its analgesic effects. Consequently, even though RB-101 is able to produce potent analgesic effects via the opioid system, it is unlikely to be addictive.
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Morphine is an endogenous opioid in humans that can be synthesized by and released from various human cells, including white blood cells. CYP2D6, a cytochrome P450 isoenzyme, catalyzes the biosynthesis of morphine from codeine and dopamine from tyramine along the biosynthetic pathway of morphine in humans. The morphine biosynthetic pathway in humans occurs as follows: L-tyrosine → para-tyramine or L-DOPA → dopamine → (S)-norlaudanosoline → (S)-reticuline → 1,2-dehydroretinulinium → (R)-reticuline → salutaridine → salutaridinol → thebaine → neopinone → codeinone → codeine → morphine (S)-Norlaudanosoline (also known as tetrahydropapaveroline) can also be synthesized from 3,4-dihydroxyphenylacetaldehyde (DOPAL), a metabolite of L-DOPA and dopamine. Urinary concentrations of endogenous codeine and morphine have been found to significantly increase in individuals taking L-DOPA for the treatment of Parkinson's disease.
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If such results occurred in humans, then it is theoretically possible for a chronic cannabis user to fail a drug test long after the usual detection time due to exercise, dieting, or severe stress shortly before the test—and several anecdotal reports of this exist. However, there is currently no hard evidence that enough active THC would be released to get one "high" or cause "flashbacks." One should also note that flashbacks from psychoactive drugs in general are now known to be psychological phenomena, and drug residues typically play no significant role in their occurrence and recurrence. As for the anecdotes about exercise, they likely experienced a "runner's high" due to their bodies releasing endorphins, which are endogenous opioid agonists, along with anandamide and other endogenous cannabinoid agonists.
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Thompson argues that addiction is universally being fostered by technology and the social environment for commercial purposes, pointing to sugar addiction from sugar-rich foods such as cupcakes, addictions to pornography, video games, shopping, and drugs such as alcohol, caffeine; illegal drugs such as cocaine and heroin, and controlled medical drugs — such as zopiclone — obtained via prescription or without one from an online pharmacy. He believes that the boundaries between everyday addictions and less socially acceptable ones are becoming increasingly blurred, and also perceives an overlap between them, citing evidence that sugar triggers "the brain's natural opioids," and that the brain can become addicted to them in the same way that it does to morphine or heroin.Colantuoni, Carlo; Rada, Pedro et al. 'Evidence that Intermittent, Excessive Sugar Intake Causes Endogenous Opioid Dependence,' Obesity Research 10, 2002.
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CI-988 (PD-134,308) is a drug which acts as a cholecystokinin antagonist, selective for the CCKB subtype. In animal studies it showed anxiolytic effects and potentiated the analgesic action of both morphine and endogenous opioid peptides, as well as preventing the development of tolerance to opioids and reducing symptoms of withdrawal. Consequently, it was hoped that it might have clinical applications for the treatment of pain and anxiety in humans, but trial results were disappointing with only minimal therapeutic effects observed even at high doses. The reason for the failure of CI-988 and other CCKB antagonists in humans despite their apparent promise in pre-clinical animal studies is unclear, although poor pharmacokinetic properties of the currently available drugs are a possible explanation, and CCKB antagonists are still being researched for possible uses as adjuvants to boost the activity of other drugs.
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It thus seems likely that while δ-opioid agonists can produce respiratory depression at very high doses, at lower doses they have the opposite effect, a fact that may make mixed mu/delta agonists such as DPI-3290 potentially very useful drugs that might be much safer than the μ agonists currently used for pain relief. Many delta agonists may also cause seizures at high doses, although not all delta agonists produce this effect. Of additional interest is the potential for delta agonists to be developed for use as a novel class of antidepressant drugs, following robust evidence of both antidepressant effects and also upregulation of BDNF production in the brain in animal models of depression. These antidepressant effects have been linked to endogenous opioid peptides acting at δ- and μ-opioid receptors, and so can also be produced by enkephalinase inhibitors such as RB-101.
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Stimulation of the periaqueductal gray matter of the midbrain activates enkephalin-releasing neurons that project to the raphe nuclei in the brainstem. 5-HT (serotonin) released from the raphe nuclei descends to the dorsal horn of the spinal cord where it forms excitatory connections with the "inhibitory interneurons" located in Laminae II (aka the substantia gelatinosa). When activated, these interneurons release either enkephalin or dynorphin (endogenous opioid neurotransmitters), which bind to mu and kappa opioid receptors on the axons of incoming C and A-delta fibers carrying pain signals from nociceptors activated in the periphery. The activation of the mu-opioid receptor inhibits the release of substance P from these incoming first-order neurons and, in turn, inhibits the activation of the second-order neuron that is responsible for transmitting the pain signal up the spinothalamic tract to the ventroposteriolateral nucleus (VPL) of the thalamus.
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" Seeing a tunnel of light can be caused by a degradation of peripheral vision brought on by extreme fear or hypoxia of the eye. The experience of meeting dead people can be brought on by a number of conditions, such as dopamine malfunction or a macular degeneration such as Charles Bonnet syndrome. A feeling of well-being could be caused by a response from the body's dopamine or endogenous opioid systems. The paper also cites a survey where it was found that approximately half of people reporting a near-death experience where not in danger of dying. In regards to Sam Parnia's near-death research, which had an objective test that involved pictures or figures hidden on shelves where a patient could not see them when lying down, but would be able to see them if having an out-of-body experience, Watt stated, "The one ‘verifiable period of conscious awareness’ that Parnia was able to report did not relate to this objective test.
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Another postulated opioid receptor is the ε opioid receptor. The existence of this receptor was suspected after the endogenous opioid peptide beta-endorphin was shown to produce additional actions that did not seem to be mediated through any of the known opioid receptors. Activation of this receptor produces strong analgesia and release of met-enkephalin; a number of widely used opioid agonists, such as the μ agonist etorphine and the κ agonist bremazocine, have been shown to act as agonists for this effect (even in the presence of antagonists to their more well known targets), while buprenorphine has been shown to act as an epsilon antagonist. Several selective agonists and antagonists are now available for the putative epsilon receptor; however, efforts to locate a gene for this receptor have been unsuccessful, and epsilon-mediated effects were absent in μ/δ/κ "triple knockout" mice, suggesting the epsilon receptor is likely to be either a splice variant derived from alternate post-translational modification, or a heteromer derived from hybridization of two or more of the known opioid receptors.
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