Exam 3: L3 Opioids Flashcards
The opioid system is one of the most complex neurotransmitter systems; plays a critical role in most biological processes of the body.
****What are the three endogenous opioids and the receptors that they bind to?
There are three endogenous opioids:
Endorphins (bind to MOR and DOR)
Enkephalins (bind to DOR)
Dynorphins (bind to KOR)
remember: EED, and MDK
What are the functions of endogenous opioids:
1.
2.
3.
Functions of endogenous opioids:
- nociception and analgesia
- mood, well being
- hedonic control (reward system)
- addictive behavior
- stress, respiration, GI transmit, reproduction, etc
**Opioid Receptors:
- opioid binding sites established in 1973
- produce _____
- Three major classes of receptors: ____, ____, and _____
- Opiates at these same receptors produce both _____ and _____
Opioid receptors are _____ distributed throughout the brain but primarily in the ____, ____,and ____
Opioid Receptors:
- opioid binding sites established in 1973
- produce analgesia
- three major classes of receptors: µ (MOR), f (DOR), and k (KOR)
- Opiates act at these same receptors to produce both analgesia and undesirable side effects
Opioid receptors are widely distributed throughout brain byt primarily in the cortex, the limbic system and the brain stem
**Opioid Receptors:
- Four ___ genes
- 7TM, receptors encode ____
- Coupled to Gi, Go
- Inhibit ____
- Results in ____ and ___
Opioid Receptors:
- Four Opr genes
- 7TM, receptors encode GPCRs
- Coupled to Gi, Go
- Inhibit PKA: Inhibition of voltage gated Ca channels and/or activation of K channels
- Results in hyperpolarization and decreased excitability
***Endogenous Opioids:
A system of _____ neurons that produce 3 genetically different opioids. All opioid peptides contain the common amino acid terminal “opioid motif” of : ____-____-____-____
They all arise from these precursors:
________———–> Endorphins
________———–> Enkephalins
________———-> Dynorphins
Endogenous Opioids:
A system of widely scattered neurons that produce three genetically different opioids. All opioid peptides contain the common amino acid terminal “opioid motif” of Tyr-Gly-Gly-Phe
They all arise from these precursors:
POMC ——–> Endorphins
Penk ———-> Enkephalins
Pdyn———–> Dynorphins
Beta-Endorphin:
Beta-Endorphin binds to ___ and ___ with high affinity
Precursor ____ is cleaved into ___ and ___
Then ____ is further cleaved into ___ and ____
Function of beta endorphin?
Beta-Endorphin:
B-Endorphin binds to MOR and DOR with high affinity
Precursor POMC is cleaved into ACTH and beta-LPH.
beta-LPH is further cleaved into a-MSH and Beta-endorphin
Function: pain modulation is a major effect, beta endorphin levels raise after oral, abdominal and gyno surgeries, reward
Enkephalins:
Enkephalins are the endogenous ligands of _____
Each pro-enk (first detected where?) Contains?
Enkephalin Function: positive regulation of hedonic homeostasis, nicotine, immune response, cardiac, aging
Enkephalins:
Enkephalins are endogenous ligands of DOR-1
Each pro-enk (first detected in adrenal medulla) contains 4 met-enk, 1 leu-enk, 1 octapeptide, and 1 heptapeptide
Endogenous Opioids: Dynorphin
Pro-dyn contains 3 main leuk-enk peptides: ____, ____ and ______
______ is the primary ligand for KOR-1
Functions: connected to stress and drug abuse
Dynorphin:
Pro-dyn contains 3 main peptides: dynorphin A, dynorphin B, and neuroendorphin
Dynorphin A is the primary ligand for KOR-1
Functions: stress and drug abuse
Endogenous Opioids: new findings
Endomorphins:
- a new class of endogenous opioids, endomorphins have been identified
- they have highest affinity and selectivity for ___
- remarkable role in neuropathic pain
Hemorphin:
- Hemorphins are generated by enzymatic cleavage of ____
- Hemorphins can inhibit ____, thus decreasing blood pressure observed after strenous exercise
Endomorphins:
- a new class of endogenous opioids
- endomorphins have the highest affinity and selectivity for MOR
- remarkable role in neuropathic pain
Hemorphin:
- hemorphin are generated by enzymatic cleavage of hemoglobin
- Hemorphin can inhibit ACE, thus decreasing blood pressure observed after strenous exercise
*****Knockout Studies:
1. MORs: essential in mediating ______and ______
(mice without MOR have _____)
- DORs: regulate _____ and _____
(mice without DOR show what?)
- KORs modulate what?
*****Knockout Studies:
- MORs: essential in mediating natural reward towards motivation and drug reinforcement
(mice without MOR have reduced adaptive behavior to drugs, withdrawl)
- DOR: regulate emotional behavior and impulsitivity
(mice without DOR have increased anxiety, depression, and increased alcohol self administration)
- KOR modulate aversive behavior, negatively modulate rewards
Endogenous Opioid Function:
- main function is _____ and _____
- neuroprotection
- respiratory depression (primarily through ____)
- Constipation
- Euphoria
- Cardioprotection
- obesity
Endogenous Opioid Function:
- main function is nociception and analgesia
- neuroprotection
- respiratory depression (primarily via MOR)
- constipation
- euphoria
- cardioprotection
- obesity
Pain:
- local anesthetics relieve pain by blocking all local sensory transmission
- in contrast, opioids work by selectively modulating pain without _______
- opioids target the ____ component of pain
- patients usually say after taking an opiate ?
Pain:
-local anesthesia relieves pain by blocking all local sensory transmission
- in contrast, opioids work by selectively modulating pain without interfering with with basic sensations
- opioids target the subjective component of pain
“The pain is still there but it does not hurt”
Nociception and Analgesia:
Mild to moderate pain is typically treated with ____
Severe pain is treated with ____
Nociception and Analgesia:
Mild to moderate pain is typically treated with NSAID
Severe pain is treated with opiates
Opiates have been used for thousands of years, first to treat diarrhea
Placebo Effect:
The placebo induced pain supression hypothesis: placebo induces release of endogenous opiates in anticipation of pain relieft
fMRI showed enhanced reponse after placebo’s in which areas of the brain?
(administration of nalaxone reduced the response in these areas…. proving the placebo effect is REAL)
Placebo effect:
in anticipation of pain relieft, after you take a placebo your body releases endogenous opioids
fMRI showed enhanced response in: gyrus, PAG, hypothalamus, rostral ventrolateral medulla
nalaxone reduced the responses in these areas
Endogenous opioids are present at the three levels of pain control:
1.
2.
3.
Endogenous opioids are present at the three levels of pain control:
- CNS
- ascending and descending pathways (spinal cord)
- target organs
Ascending Pain pathways:
- fast pain: _____ released from ____ fibers
- slow pain: _____ released from ___ fibers
There are opioid containing interneurons in the dorsal horn that terminate where the pain afferents terminate. These interneurons have a ______ action on the pain afferents.
Opioids _____ ascending pain transmission
Ascending pain pathways:
- fast pain: glutamate released from Adelta fibers
- slow pain: sub P released from C fibers
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.
Opioids reduce ascending pain transmission
******* Opioid dependent pain modulation is regulated at the _____, through the ____ and _____
******
Opioid dependent pain modulation is regulated at the PAG, through the RVM and DLPT
Descending pain supression:
The endogenous opioid system modulates descending pain pathway via PAG
opioids ____ the release of GABA, thus activating the ____and ____
Descending pain pathway:
opioids inhibit the release of GABA, thus activating the PAG and the NRPG
Anti-nociceptive Effects:
Presynaptic stimulation of opioid receptor by enkephalins from interneurons does what
Anti-nociceptive Effects:
Presynaptic stimulation of opioid receptor by enkephalins from interneurons INHIBITS release of pro-nociceptive peptides such as substance P and CGRP
******Hedonic Control:
Pleasure and mood are controlled at the area of the brain called the _________ by inputs mediated by opioid receptors from:
(Explain what is important in these areas):
PFC
VTA
hippocampus
amygdala
****Hedonic control:
Pleasure and mood are controlled at the area of the brain called the nucleus acumbens by inputs mediated from opioid receptors from:
PFC (planning, impulse, decision)
VTA (motivation)
hippocampus (memory)
amydgala (emotion and sexual performance)
Opioids and Alcohol:
Alcohol enduces activation of endogenous opioid system
Clinical trials have showed that the administration of _____ causes:
decreased average number of days you drink
decreased desire to drink
decreased alcohol induced high
Opioids and Alcohol:
Alcohol enduces activation of endogenous opioid system:
Clinical trials have showed that the administration of opioid antagonis naloxone causes:
decreased desire to drink and decreased alcohol induced high
Clinical Relevance:
Pain relief:
The use of exogenous opioids for pain relief has limitations due to their undesirable adverse effects: ____, _____, and ____
Drugs that bind to ____ lack those respiratory and gastro side effects
Pain Relief:
The use of exogenous opioids for analgesia has limitations due to their undesirable side effects: sedation, constipation, decreased respiration
Drugs that bind to DOR lack those respiratory and gastro side effects
Opium:
-derived from poppy seeds
- sedation, pain relief, and euphoria
- active agent is ____, the most widely used pain killer to date
Opium:
derived from poppy seeds
sedation, pain relief, euphoria
-Active agent is morphine, the most widely used pain killer to date
******What is the difference between morphine and heroin?
Heroin:
Made from the diacetylation of morphine
that diacetylation causes 3x the potency
STRONGLY addictive
*****Hedonic control and addiction
CNS opioids modulate _____ and other NTs that control hedonic drives
Opioid control of brain _____ is crucial in motivated behavior and addiction
CNS opioids modulate dopamine, and other NTs that control hedonic drives
Opioid control of brain dopamine is crucial in motivated behavior and addiction
