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7/27/2019 Opioid Drugs, Opioid Receptors-e-Notes and Video Tutorials
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Opioid Drugs and Opioid Receptors e-Notes
and Video Tutorials
Image Source:http://www.cnsforum.com/educationalresources/imagebank//default.aspx
Opioid Drugs and Opioid receptors e-Notes|
FromIVMS| Marc Imhotep Cray, M.D.
A. Definitions
1. Opioids are drugs with morphine-like activity that produce analgesia (i.e., reduce
pain) without the loss of consciousness and can induce tolerance and physical
dependence. Opioids are also referred to as narcotic analgesics.
2. Opiates are drugs derived from opium (e.g., morphine, heroin), a powdered, dried
exudate of the fruit capsule (poppy) of the plant Papaver somniferum. Opium alkaloids
(e.g., thebaine) are used to make semisynthetic opioids. Other opioids are prepared
synthetically (e.g., methadone).
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3. Opiopeptins (endogenous opioid peptides) are natural substances of the body that
have opioid-like activity.
a. Opiopeptins are localized in discrete areas of the CNS and in a number of peripheral
tissues including the GI tract, kidney, and biliary tract.
b. Opiopeptins are derived from distinct polypeptide precursors.
(1) Preproopiomelanocortin contains b-endorphin (also adrenocorticotropic hormone
[ACTH] and melanocyte-stimulating hormone).
(2) Preproenkephalin contains the pentapeptides met-enkephalin and leu-enkephalin.
(3) Preprodynorphin contains dynorphins A and B and neoendorphins a and b.
B. Mechanism of action
1. Opioids such as morphine are believed to mimic the effects of opiopeptins by
interaction with one or more several distinct receptors (l, j, d). Each opioid receptor has
distinct subtypes (e.g., l1, l2). Opioids with mixed agonistantagonist properties may act
as agonists at one opioid receptor and antagonists at another (e.g., pentazocine) or as
partial agonists (e.g., buprenorphine).
a. Interaction with l-receptors contributes to supraspinal and spinal analgesia,
respiratory depression, sedation, euphoria, decreased GI transit, and physical
dependence.
b. Interaction with j-receptors contributes to supraspinal and spinal analgesia, sedation,
and miosis.
c. The significance of interaction with d-receptors is unclear, but it may contribute to
analgesia.
d. b-Endorphins, the enkephalins, and dynorphins have their highest affinity for,
respectively,l, d, and j receptors.
2. Opioids produce analgesia and their other actions by mechanisms that are not
completely understood.
a. All opioids activate inhibitory guanine nucleotide binding proteins (Gi).
b. Opioids inhibit adenylyl cyclase activity, resulting in a reduction in intracellular cAMP
and decreased protein phosphorylation.
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c. Opioids promote the opening of potassium channels to increase potassium
conductance, which hyperpolarizes and inhibits the activity of postjunctional cells.
d. Opioids close voltage-dependent calcium channels on prejunctional nerve terminals
to inhibit release of neurotransmitters (e.g., the release of glutamate and the release of
substance P in the spinal cord).
e. Opioids raise the threshold to pain by interrupting pain transmission through
ascending pathways (substantia gelatinosa in the dorsal horn of the spinal cord, ventral
caudal thalamus) and activating the descending modulatory pathways (periaqueductal
gray area in the midbrain, rostral ventral medulla) in the CNS.
f. Opioids also raise the threshold to pain by action on peripheral sensory neurons.
g. Opioids decrease emotional reactivity to pain through actions in the limbic areas of
the CNS.
C. Psychologic dependence and compulsive drug use
1. The euphoria and other pleasurable activities produced by opioid analgesics,
particularly when self-administered intravenously, can result in the development of
psychologic dependence with compulsive drug use. This development may be
reinforced by the development of physical dependence.
2. Although physical dependence is not uncommon when opioids are used for
therapeutic purposes, psychologic dependence and compulsive drug use are not.
D. Tolerance and physical dependence
1. Tolerance
a. Tolerance occurs gradually with repeated administration; a larger opioid dose is
necessary to produce the same initial effect.
b. Tolerance is due to a direct neuronal effect of opioids in the CNS (i.e., cellular
tolerance).
c. Tolerance varies in degree.
d. Tolerance can be conferred from one opioid agonist to others (cross-tolerance).
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2. Physical dependence occurs with the development of tolerance to opioids.
a. Abstinent withdrawal
(1) Abstinent withdrawal is a syndrome revealed with discontinuation of opioid
administration.
(2) Abstinent withdrawal is characterized by drug-seeking behavior and physical signs
ofautonomic hyperexcitability that may include goose bumps (going cold turkey).
Morphine: prototype
1. Pharmacologic properties
a. Morphine is usually given parenterally, but it can be given orally or rectally.
b. Morphine undergoes extensive first-pass metabolism with glucuronide conjugation
(morphine-6-glucuronide may possess analgesic activity). Dosage adjustment of
morphine is necessary in patients with hepatic insufficiency.
c. Morphine has a plasma half-life (t1/2) of 23 hours; its duration of action is 36 hours.
2. Therapeutic uses of morphine and other opioids
a. Analgesia
(1) Morphine is used for analgesia in severe preoperative and postoperative pain, as
well as for the pain of terminal illness; it is used to treat the visceral pain of trauma,
burns, cancer, acute myocardial infarction (MI), and renal or biliary colic. Higher doses
are necessary for intermittent sharp pain.
(2) Morphine produces analgesia by increasing the threshold for the sensation of pain
and by dissociating the perception of pain from the sensation. There is significant
interpatient variability in this latter effect.
(3) In addition to analgesia, decreased anxiety, sedation that is marked by drowsiness,
inability or decreased ability to concentrate, loss of recent memory, and occasional
euphoria are useful additional properties of morphine in frightening disorders, such as
MI and terminal illness.
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b. Diarrhea
(1) The antidiarrheal effect of morphine is a pharmacologic extension of its constipating
effect (see below). For this reason, morphine is often used after an ileostomy or
colostomy.
(2) Morphine is an effective treatment for diarrhea at a less-than-analgesic dose.
(3) Codeine is popular because of its reduced abuse liability. Diphenoxylate (with
atropine to reduce the likelihood of parenteral use) and loperamide are used widely,
because at therapeutic doses, their actions are confined primarily to the GI tract and
because their insolubility precludes IV use.
(4) No significant development of tolerance occurs to the antidiarrheal action of
morphine.
c. Acute pulmonary edema
(1) Morphine relieves the dyspnea (feeling of shortness of breath and the struggle to
breathe) associated with acute pulmonary edema secondary to left ventricular failure.
(2) This effect may be due to 1) decreased peripheral resistance with a decreased
afterload and decreased venous tone with a decreased preload; 2) decreased anxiety of
the patient; and/or 3) depression of the respiratory center and the CNS response to
hypoxic drive.
d. Myocardial infarction. Vasodilation and the subsequent decreased cardiac preload
are of additional therapeutic benefit when morphine is used for the pain of MI.
Pentazocine and butorphanol increase preload and are contraindicated for the
treatment of MI.
e. Cough
(1) Opioids are used to produce a direct depression of the cough center in the medulla
when the cough is not controlled by nonopioids. Codeine, at a subanalgesic dose, is
widely used for severe cough.
(2) The receptors are unique in that the cough reflex is depressed by both L-isomers
and Disomers of opioids (D-isomers are without analgesic action).
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f. Anesthesia applications
(1) Preanesthetic medication or supplement to anesthetic agents during surgery
(a) Opioids are used for analgesic and sedative or anxiolytic effects.
(b) Fentanyl is often used for its short duration of action relative to morphine.
(2) Regional analgesia (epidural or intrathecal administration)
(a) Morphine and fentanyl are used to achieve long-lasting analgesia that is mediated
through action on the spinal cord.
(b) There is a reduced incidence of adverse effects, but delayed respiratory depression,
nausea, vomiting, and pruritus often occur.
(3) High-dose fentanyl or congeners (or morphine) are used as primary anesthetic in
cardiovascular surgery because of their minimal cardiac depression.
g. Physical dependence. Opioids (methadone, buprenorphine) are used to mitigate the
withdrawal symptoms of physical dependence caused by other opioids, including
heroin.
3. Adverse effects and contraindications of morphine and other opioids
a. Respiratory depression
(1) Respiratory depression is generally not a serious clinical problem except in several
special circumstances.
(2) Respiratory depression with opioid use is due to the direct inhibition of the
respiratory center in the brainstem and to decreased sensitivity of the respiratory center
to CO2 with decreased hypoxic drive; it leads to decreased respiratory rate, minute
volume, and tidal exchange.
(3) Opioids are contraindicated if there is a preexisting decrease in respiratory reserve
(e.g., emphysema) or excessive respiratory secretions (e.g., obstructive lung disease).
(4) These drugs are contraindicated in patients with head injury. Cerebral vasodilation
results from the increased pCO2 caused by respiratory depression and may result in
increased cerebral vascular pressure, which may lead to exaggerated respiratory
depression and altered brain function.
(5) Opioids should be used cautiously during pregnancy because they may prolong
labor and cause fetal dependence.
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(6) Clinical or accidental opioid overdose with respiratory depression may be treated
with artificial ventilation; this may be sufficient for the treatment of respiratory
depression or coma. Opioid antagonists can be used to reverse respiratory depression.
b. Constipation
(1) Constipation results from increased tone with decreased coordinated GI motility,
increased anal sphincter tone, and inattention to the defecation reflex.
(2) This effect is mediated through actions on the GI tract, to inhibit release of
acetylcholine, and on the CNS.
(3) There is no clinically significant tolerance to this effect.
c. Hypotension
(1) Opioids inhibit the vasomotor center in the brainstem, causing peripheral
vasodilation; they also inhibit compensatory baroreceptor reflexes and increase
histamine release.
(2) Opioids should be used cautiously in patients in shock or with reduced blood
volume.
The elderly are particularly susceptible.
d. Nausea and vomiting
(1) This common effect of opioids is caused by the direct stimulation of the
chemoreceptor trigger zone (CTZ) in the area postrema of the medulla, which leads to
activation of the vomiting center; there is also a direct vestibular component.
(2) This effect is blocked by dopamine-receptor antagonists.
(3) This effect is self-limiting because of the subsequent direct inhibition by morphine of
the vomiting center.
e. Pneumonia is a potential result of a reduced cough reflex when opioids are used for
analgesia, particularly when respiration is compromised.
f. Sedative activity with drowsiness places ambulatory patients at risk for accidents. A
paradoxical dysphoria occasionally develops.
g. Pain from biliary or urinary tract spasm
(1) This pain is due to the increased muscle tone of smooth muscle in the biliary tract,
the sphincter of Oddi, and the ureters and bladder.
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(2) These spasms may result in a paradoxical increase in pain when opioids are used to
alleviate the pain associated with the passing of urinary or biliary stones if the dose is
insufficient to induce centrally mediated analgesia.
h. Urine retention
(1) This effect, more common in the elderly, is due primarily to decreased renal plasma
flow. Other contributing factors include increased tone with decreased coordinated
contractility of the ureters and bladder, increased urethral sphincter tone, and inattention
to the urinary reflex.
(2) Catheterization is necessary in some instances.
(3) Opioids should be used cautiously in patients with prostatic hypertrophy or urethral
stricture.
i. Psychologic or physical dependence. The risk for the development of psychologic
dependence or physical dependence is not a valid excuse to withhold opioids and
thereby provide inadequate relief from pain, particularly in the terminally ill.
j. Miosis
(1) Opioid stimulation of the Edinger-Westphal nucleus of the oculomotor nerve results
in pinpoint pupils even in the dark. This effect is mediated by acetylcholine and
blocked by atropine.
(2) No tolerance develops to this effect.
(3) During severe respiratory depression and asphyxia, miosis may revert to mydriasis.
4. Drug interactions
a. Drugs that depress the CNS add to or potentiate the respiratory depression caused
by opioids (e.g., sedativehypnotic agents).
b. Antipsychotic and antidepressant agents with sedative activity potentiate the sedation
produced by opioids.
c. In the presence of opioids, particularly meperidine, MAOIs produce severe
hyperthermia, seizures, and coma.
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2. Fentanyl, sufentanil, alfentanil, remifentanil
a. Fentanyl and other subtypes are administered parenterally. They have a shorter
duration of action than morphine. Remifentanil is rapidly metabolized by blood and
tissue esterases.
b. Fentanyl is available as a transdermal patch and lozenge on a stick for breakthrough
cancer pain.
c. Fentanyl is administered as a preanesthetic and intraoperative medication for its
analgesic, anxiolytic, and sedative properties.
d. Fentanyl (or morphine) is used in high doses as a primary anesthetic for
cardiovascular surgery because it produces minimal cardiac depression.
e. Fentanyl is used to supplement the analgesia and sedativehypnotic effects of
nitrous oxide and halothane in a balanced anesthesia approach. Morphine also is
used for this indication.
f. Fentanyl is infrequently used in the combination product fentanyl/droperidol
(Innovar) to induce neuroleptanalgesia. This combination permits a wakeful state
when patient cooperation is needed (intubations, minor surgical procedures, changing
burn dressings).
g. These drugs may cause severe truncal rigidity when administered by rapid IV at a
high dose.
3. Methadone (also levomethadyl acetate)
a. Methadone, like morphine, has good analgesic activity. It is administered orally and
has a longer duration of action than morphine.
b. Methadone is associated with a less severe withdrawal syndrome than morphine; it is
often substituted for other opioids as a treatment for physical dependence because it
allows a smoother withdrawal with tapered dose reduction. It is also used for
maintenance therapy of the heroin-dependent addict.
4. Meperidine
a. Meperidine has a shorter duration of action than morphine.
b. Meperidine appears to produce less neonatal respiratory depression than morphine
and may be preferred in obstetrics.
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c. High doses may cause CNS excitation (tremors, delirium, hyperreflexia) and seizures
due to formation of a metabolite, normeperidine.
d. Meperidine causes severe restlessness, excitement, and fever when administered
with MAOIs.
e. Meperidine use may result in mydriasis and tachycardia due to weak anticholinergic
activity.
f. Meperidine has no effect on the cough reflex.
G. Weak agonists
1. Codeine, oxycodone, and hydrocodone are partial opioid receptor agonists used
for moderate pain.
a. They are orally effective and undergo less first-pass metabolism than morphine.
b. These drugs are usually used in combination with other analgesics such as
acetaminophen, aspirin, or ibuprofen (e.g., codeine/acetaminophen = Tylenol with
codeine; hydrocodone/ acetaminophen = Vicodin, Lortab; oxycodone/aspirin =
Percodan; and oxycodone/acetaminophen = Percocet).
c. These drugs are associated with less respiratory depression than morphine and have
less dependence liability. Overdose with codeine produces seizures.
2. Propoxyphene
a. Propoxyphene is used as an analgesic; however, it has lower efficacy than codeine. It
is usually used in combination with aspirin or acetaminophen.
b. Propoxyphene has low abuse liability but can produce respiratory depression and
dependence.
c. Propoxyphene may cause seizures at high doses.
H. Mixed agonistantagonists/Partial agonists
1. Buprenorphine, pentazocine, nalbuphine, and butorphanol
a. Buprenorphine is a partial agonist at opioid l-receptors.
b. Pentazocine, nalbuphine, and butorphanol are opioid j-receptor agonists with partial
agonist or antagonist activity at opioid l-receptors.
2. These drugs are used for moderate pain.
3. Buprenorphine, like methadone, is used for heroin detoxification.
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4. Severe respiratory depression, although uncommon, is resistant to naloxone reversal.
5. These drugs have less dependence liability than morphine.
6. These drugs, except nalbuphine, can increase cardiac preload and should not be
used to treat the pain of MI.
7. These drugs can precipitate withdrawal if administered to patients already receiving
strong opioid agonists.
8. Pentazocine occasionally causes dysphoria, hallucinations, and depersonalization
and is not commonly used in clinical practice.
I. Tramadol
1. In addition to weak opioid l-receptor agonist activity, tramadol also weakly blocks
reuptake of serotonin and norepinephrineeffects that appear to account for its
analgesic action.
2. It may have special use for neuropathic pain.
3. Tramadol is associated with an increased risk of seizures and is contraindicated in
patients with epilepsy.
4. Its actions are only partially reversed by naloxone.
5. Tramadol should not be administered to patients taking MAOIs.
J. Opioid antagonists
1. Naloxone and naltrexone (also nalmefene) are competitive inhibitors of the actions of
opioids.
2. These drugs will precipitate opioid withdrawal.
3. Naloxone has a relative short duration of action of 12 hours. It is used to diagnose
opioid dependence and to treat acute opioid overdose. Because of its short duration of
action, multiple doses may need to be administered.
4. Naltrexone has duration of action of up to 48 hours. It is approved for use to help
decrease craving for alcohol.
K. Antidiarrheal agents
1. Diphenoxylate/atropine, difenoxin, and loperamide are taken orally for the
symptomatic treatment of diarrhea.
2. Diphenoxylate is only available combined with atropine to minimize parenteral
misuse.
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3. Insolubility of diphenoxylate limits its absorption across the GI tract. Loperamide does
not penetrate the brain.
4. These drugs have minimal dependence liability or other centrally mediated opioid-like
effects at therapeutic doses.
L. Antitussive agents
1. Dextromethorphan, an opioid isomer, is an over-the-counter cough medication that,
like codeine, is used for its antitussive activity. However, it has little or no analgesic or
addictive properties at therapeutic doses. Some constipation and sedation have been
noted.
Links:
http://en.wikipedia.org/wiki/Opioid Opioid Withdrawal SymptomsInformation about Opioid and opiate withdrawal
issues The use of opioids for chronic pain @ The APS World Health Organization guidelines for the availability and accessibility of
controlled substances Video: Opioid side effects(Vimeo)(YouTube)A short educational film about the
practical management of opioid side effects.
Book: Katzung, B. Basic and Clinical Pharmacology. 11th ed. McGraw Hill Medical,2009
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Opioid receptors Video|
FromPharmacology Corner| By Flavio Guzmn, MD.
A video on Mu, Delta, Kappa and ORL1 receptors
Source:http://pharmacologycorner.com/opioid-receptors/
By Flavio Guzmn, MDThis lecture discusses the following topics:
General classification Cellular actions of opioid receptors Anatomical distribution and physiologic effects of mu, delta and kappa receptors Agonists and antagonists
http://en.wikipedia.org/wiki/Opioidhttp://en.wikipedia.org/wiki/Opioidhttp://www.painpillabuse.com/http://www.ampainsoc.org/advocacy/opioids.htmhttp://www.ampainsoc.org/advocacy/opioids.htmhttp://www.who.int/medicines/areas/quality_safety/GLs_Ens_Balance_NOCP_Col_EN_sanend.pdfhttp://www.who.int/medicines/areas/quality_safety/GLs_Ens_Balance_NOCP_Col_EN_sanend.pdfhttp://www.who.int/medicines/areas/quality_safety/GLs_Ens_Balance_NOCP_Col_EN_sanend.pdfhttp://www.who.int/medicines/areas/quality_safety/GLs_Ens_Balance_NOCP_Col_EN_sanend.pdfhttp://www.who.int/medicines/areas/quality_safety/GLs_Ens_Balance_NOCP_Col_EN_sanend.pdfhttp://vimeo.com/46549874http://vimeo.com/46549874https://www.youtube.com/watch?v=1IrJk4780gchttps://www.youtube.com/watch?v=1IrJk4780gchttp://pharmacologycorner.com/opioid-receptors/http://pharmacologycorner.com/opioid-receptors/http://pharmacologycorner.com/opioid-receptors/http://pharmacologycorner.com/opioid-receptors/http://pharmacologycorner.com/opioid-receptors/http://pharmacologycorner.com/opioid-receptors/http://pharmacologycorner.com/opioid-receptors/http://pharmacologycorner.com/opioid-receptors/https://www.youtube.com/watch?v=1IrJk4780gchttp://vimeo.com/46549874http://www.who.int/medicines/areas/quality_safety/GLs_Ens_Balance_NOCP_Col_EN_sanend.pdfhttp://www.who.int/medicines/areas/quality_safety/GLs_Ens_Balance_NOCP_Col_EN_sanend.pdfhttp://www.ampainsoc.org/advocacy/opioids.htmhttp://www.painpillabuse.com/http://en.wikipedia.org/wiki/Opioid7/27/2019 Opioid Drugs, Opioid Receptors-e-Notes and Video Tutorials
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ORL-1 receptors
Part 1: Classification and cellular actions
Provides an introduction to the classification of opioid receptors, it also discusses the
cellular effects of opioid receptor activation (presynaptic inhibition of neurotransmitterrelease)
Part 2:Mu, kappa and delta receptors (including agonists and antagonists)
Part 2 lists the most relevant agonists and antagonists for the different subtypes ofopioid receptor, then effects upon activation (opioid physiology) are reviewed.
https://www.youtube.com/watch?feature=player_embedded&v=YCz5A8ZkavMhttps://www.youtube.com/watch?feature=player_embedded&v=YCz5A8ZkavMhttps://www.youtube.com/watch?feature=player_embedded&v=LT80LeQNO10https://www.youtube.com/watch?feature=player_embedded&v=LT80LeQNO10https://www.youtube.com/watch?feature=player_embedded&v=YCz5A8ZkavMhttps://www.youtube.com/watch?feature=player_embedded&v=LT80LeQNO10https://www.youtube.com/watch?feature=player_embedded&v=YCz5A8ZkavM7/27/2019 Opioid Drugs, Opioid Receptors-e-Notes and Video Tutorials
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https://www.youtube.com/watch?feature=player_embedded&v=LT80LeQNO107/27/2019 Opioid Drugs, Opioid Receptors-e-Notes and Video Tutorials
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Part 3:ORL1, nociceptin or orphanin FQ receptor
Part 3 is an overview on the recently discovered ORL1 receptor.
https://www.youtube.com/watch?feature=player_embedded&v=JG5eKqPlIN4https://www.youtube.com/watch?feature=player_embedded&v=JG5eKqPlIN4https://www.youtube.com/watch?feature=player_embedded&v=JG5eKqPlIN4https://www.youtube.com/watch?feature=player_embedded&v=JG5eKqPlIN47/27/2019 Opioid Drugs, Opioid Receptors-e-Notes and Video Tutorials
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PowerPoint presentation
If you prefer to review the figures at your own pace you can review the PPT slide byslide:
References and further reading
Katzung, B. Basic and Clinical Pharmacology. 11th ed. McGraw Hill Medical, 2009
Koneru A, Sreemantula S, Rizwan. Endogenous Opioids: Their Physiological Role andReceptors. Global J. Pharmacol., 3 (3): 149-153, 2009
McDonald J, Lambert DJ. Opioid Receptors. Continuing Education in Anaesthesia,Critical Care & Pain 2005 5:1
Trescot A, Sukdeb D. Opioid Pharmacology. Pain Physician 2008; 11:S133-S153
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http://www.slideshare.net/flaviog/ops-8849962?ref=http://pharmacologycorner.com/opioid-receptors/http://www.slideshare.net/flaviog/ops-8849962?ref=http://pharmacologycorner.com/opioid-receptors/http://www.slideshare.net/flaviog/ops-8849962?ref=http://pharmacologycorner.com/opioid-receptors/http://www.slideshare.net/flaviog/ops-8849962?ref=http://pharmacologycorner.com/opioid-receptors/