Term
| endogenous opioid peptides |
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Definition
endomorphins
enkephalins
endorphins
dynorphins |
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Term
| what receptors do the endogenous opioids (endorphins, endomorphins, dynorphins, and enkephalins) bind to? |
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Definition
endogenous opioids have affinity for opioid receptors, although their affinity tends to vary
endorphins: mu = delta, little affinity for kappa
endomorphins: mu
dynorphins: kappa, mu, delta
enkephalins: delta > mu |
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Term
| generation of endogenous opioids |
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Definition
the dynorphins, enkephalins, and endorphins are encoded by 3 distinct genes
from DNA, transcription takes place in the nucleus, resulting in mRNA
the mRNA is then transported to the cytosol to where ribosomes bind to it, initiating translation resulting in generation of the prepropeptide
the preprepeptide has a signal peptide which targets the prepropeptide to the endoplasmic reticulum
once in the endoplasmic reticulum, the signal peptide is cleaved off by signal peptidases, resulting in the propeptide
they are then transported to the Golgi, where they are sorted and packaged into secretory vesicles
once packaged into vesicles along with specific cleaving enzymes, they undergo further processing (cleavage, glycosylation, amidation) within the secretory vessicle
the end produce is released from the cell by exocytosis |
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Term
| generation of endorphins (stress and synthesis of endorphins) |
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Definition
endorphins are generated from the prepropeptide, preproopiomelanocortin
after the signal sequence is cleaved off by signal peptidases, this results in generation of the propeptide, pro-opiomelanocortin (POMC)
POMC can encode many different peptides. however, the peptide generated depends on how the propeptide is cleaved
the cleavage varies depending upon which enzymes are present (which can vary with location)
the anterior pituitary has a high amount of POMC and mRNA
in the anterior pituitary, POMC is cleaved into several different fragments, ACTH, and beta-lipotropin
beta-lipotropin is further cleaved into beta endorphin and gamma lipotropin
the link between ACTH and beta-endorphin suggests an association between stress-induced analgesia, as stress causes for release of ACTH, which then acts on the adrenal medulla to increase cortisol
in fact, stressors in animals can increase POMC, mRNA, resulting in increased generation of beta endorphins and ACTH
conversely, the use of corticosteroids such as dexamethasone can lower POMC |
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Term
| runner's high, an opioid link? |
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Definition
Boecker study:
people report how they felt before and after they ran using a mood scale, with the lower number being unhappy
following running, they then used a non specific opioid receptor radioligand to see how the runner's mood following running correlated with opioid binding within 3 areas of the brain involved in emotion using PET
they found a correlation between decreased opioid receptor binding using PET and improved mood following running
thre result suggests that there is a link between endogenous opioids mediating the improved mood or runner's high, as endogenous opioid would be expected to competitively reduce binding of the radioligand and that this correlated well with the improved mood |
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Term
| generation of enkephalins |
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Definition
similar to endorphins, the enkephalins are generated from preproenkephalin
once in the ER, the signal peptide is celaved to generate proenkephalin
proenkephalin has multiple sequences for enkephalin subtypes |
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Term
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Definition
similarly, the dynorphins are generated from preprodynorphin
once in the ER, the signal peptide is cleaved to generate prodynorphin
prodynorphin can be cleaved to generate many different dynorphin peptides such as dynorphin A and B |
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Term
| affinity of dynorphin analogs for kappa receptors |
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Definition
Dyn A 1-17 > big-Dyn = Dyn B = Dyn B 1-29 = alpha-neo-endorphin > Dyn A 1-8 = beta-neo-endorphin
DYN A 1-17 = MOST POTENT
dynorphin has dose dependent effects!
at low concentrations dynorphin produces analgesic effect
however, at higher concentrations, dynorphin has pro-nociceptive effect replicating some of the features of neuropathic pain |
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Term
| dynorphin and neuropathic pain |
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Definition
nerve ligation model:
used to figure out the mechanism of chronic neuropathic pain
lesion the L5/L6 spinal nerves of a rat on one side resulting in mechanical allodynia (enhanced responsiveness to innoxious stimuli) and thermal hyperalgesia (enhanced responsiveness to noxious stimuli)
they can then look at treatments and mechanisms by why neuropathic pain develops, the efficacy of treatment, and interventions that may be useful in the clinic
only one side is lesions so that the rat has its own built-in control as you can assess how the rat responds to non-noxious or noxious stimuli |
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Term
| mechanism of L5/L6 nerve ligation resulting in mechanical allodynia and thermal hyperalgesia |
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Definition
at threshold, the animal responds by quickly flicking its paw away from the filament.
mechanical withdrawal threshold is defined as the minimum gauge wire stimulus that elicits withdrawal reaction
the paw withdrawal threshold for the rats with intact nerves is 15g
in contrast, the rats with spinal nerve ligation have a reduced threshold to where it takes significantly less mechanical force for them to withdraw their paw (3g), demonstrating mechanical allodynia
L5/L6 nerve ligated rats respond much more quickly to the noxious heat stimulus also, demonstrating thermal hyperalgesia |
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Term
| dynorphin levels after L5/L6 nerve ligation |
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Definition
mechanisms that underlie development of neuropathic pain
levels of dynorphin A 1-17 in the spinal cord following L5/L6 nerve ligation:
no change in the spinal cord of the nerve ligated rats EXCEPT there is an SIGNIFICANT INCREASE in dynorphin A 1-17 in the ipsilateral dorsal horn of the L5/L6 nerve ligated rat (area of the spinal cord where the nerve was ligated)
this suggests that the increased dynorphin levels may underlie some of the features of neuropathic pain
why no changes in the ipsilateral ventral portion of the spinal cord?
b/c motor neurons reside in the ventral portion of the spinal cord. in contrast, sensory neurons (including those that encode nocieption) reside in the dorsal horn |
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Term
| it is suggested that dynorphin A 1-17 is elevated following nerve ligation, what happens if dynorphin is administered? |
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Definition
administration of dynorphin can reproduce some features of neuropathic pain
prior to administration of dynorphin, paw withdrawal thresholds were normal
however, following intrathecal dynorphin, paw withdrawal thresholds dropped significantly, demonstrating mechanical allodynia
even more interesting is that mechanical allodynia persisted for 60 days after after the one time administration of dynorphin!
dynorphin A 1-17 can produce long-lasting mechanical allodynia |
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Term
| NMDA receptor antagonists can block the effects of dynorphin |
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Definition
dynorphin can result in mechanical allodynia
data suggests that dynorphin may be involved in central sensitization, as central sensitization results in mechanical allodynia
central sensitization:
increase in the excitability and synaptic efficacy of neurons in the central nociceptive pathways
NMDA receptors are shown to be an important contributor to central sensitization (central sensitization can be blocked by using a NMDA receptor antagonist)
rats receive dynorphin + NMDA antagonist = no statistically significant difference in mechanical thresholds
rats just receiving dynorphin = protracted mechanical allodynia
dynorphin may bind to the glycine site of the NMDA receptor |
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Term
| effect of dynorphin antiserum on mechanical allodynia and thermal hyperalgesia |
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Definition
it has been demonstrated that dynorphin produces long lasting mechanical allodynia and is elevated in neuropathic pain
can dynorphin anti-serum prevent mechanical allodynia and thermal hyperalgesia following nerve ligation?
dynorphin anti-serum: binds up dynorphin and blocks its action
rats with L5/L6 ligations treated with dynorphin anti-serum:
no impact on mechanical allodyina
however, THERMAL HYPERALGESIA was inhibited by dynorphin anti-serium following nerve injury |
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Term
| most endogenous opioids share a common NH2 sequence except: |
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Definition
endomorphins
one of the common features of most endogenous opioids is that they share a similar amino terminal sequence of Tyr-Gly-Gly-Phe with Leu or Met
this has been termed an opioid motif and thought to underlie opioid receptor binding
enkephalins, dynorphins, and endorphins have a peptide precursor
a new family of endogenous opioid, the endomorphins, has a yet to be discovered precursor
the endomorphins are a bit different than most of the other endogenous opioids in that they don't share the similar amino terminal sequence
instead they have :
endomorphin 1 = Tyr-Pro-Trp-Phe
endomorphin 2 = Tyr-Pro-Phe-Phe
they are also a bit unusual that instead of being full agonists at the opioid receptors (like the other endogenous opioids) they are partial agonists |
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Term
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Definition
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Term
| important pharmacological effects mediated by the mu opioid receptors and location |
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Definition
analgesia (central)
euphoria (central)
respiratory depression
anti-diarrheal effects (peripheral)
localization of receptors:
periaquaductal gray
thalamus
spinal cord
enteric smooth muscle |
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Term
| important pharmacological effects mediated by delta opioid receptors and location |
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Definition
analgesia
localization of receptors:
spinal cord
PAG/RVM |
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Term
| important pharmacological effects mediated by kappa opioid receptors and location |
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Definition
analgesia
dysphoria (central)
localization of receptors:
cortex
PAG/RVM
spinal cord |
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Term
| receptor activity of agonists opioid drugs |
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Definition
[image]
opioid receptor agonists are drugs that activate opioid receptors
their activation is associated with binding to the Gi subtype of GPCRs -> results in inhibition of adenylyl cyclase and consequently a decrease in intracellular cAMP
agonists have high intrinsic activity, meaning that they have the ability to activate the receptor to produce an effect
for agonists, with increasing dose you can see a dose related increase in the effect that reaches a maximal effect
most of the opioid receptor agonists have greater affinity (and activity) for the mu opioid receptor subtype |
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Term
| receptor activity of mixed opioid receptor agonists |
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Definition
[image]
mixed opioid receptor agonists are drugs that activate one receptor subtype (agonists) and are antagonists (or partial agonists) at another receptor subtype
most of the drugs in this group are mu receptor partial agonists and kappa receptor agonists
howevere, the partial agonist activity at the mu receptor can antagonize the effects of full agonists
mixed opioid receptor agonists, if they're partial agonists have less intrinsic acitivty than a full agonist to where their effects are lessened compared to a full agonist |
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Term
| receptor activity of opioid receptor antagonists |
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Definition
[image]
opioid receptor antagonists block action of agonist drugs or in some cases may block action of endogenous opioid peptides
in contrast to agonists and partial agonists, they have no intrinsic activity
they solely block the receptor site
all of the opioid receptor antagonists are competitive antagonists
if you have an agonist, addition of an antagonist will shift the dose response curve to the right
giving an antagonist or even a mixed agonist can cause withdrawal symptoms (precipitated withdrawal) |
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Term
opioid differ in their potency.
potency is influenced by: |
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Definition
pharmacokinetic factors
affinity for receptors
potency is influenced by pharmacokinetic factors (i.e. how much of the drug enters the body systemic circulation and then reaches the receptors, or lipophilicity of the drug) and by affinity to drug receptors
many of the very potent opioids are highly lipophilic
[image]
R = fentanyl
S = morphine
T = pentazocine (partial agonist activity on mu receptor)
for fentanyl, it takes significantly less of the drug to produce analgesia
morphine, which is less potent it is going to take more agonist to produce the same measurable effect
for a partial agonist such as pentazocine, it is going to take more of the drug (curve shifts right) and there is not going to be a maximal analgesic response |
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Term
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Definition
opioids bind to opioid receptors (GPCRs coupled to Gi)
binding inhibits adneylyl cyclase, leading to a reduction in cAMP
opioid receptor activation is also coupled to receptor linked K+ currents and suppression of voltage gated Ca channels
increasing K+ efflux can hyperpolarize the neuron (less likely to reach threshold and fire an action potential)
if voltage gated Ca channels are inhibited, NTs cannot be released
thus, opioid can interfere with neurotransmission of nociceptive information in a few different ways |
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Term
| mu opioid receptor subtypes |
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Definition
mu1 and mu2 receptors
mu1 and mu2 receptors both mediate analgesia
only m2 mediates respiratory depression and constipation |
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Term
| opioid receptors can form heterodimers altering their pharmacological properties |
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Definition
mu1 and mu2 receptors were discovered based on their affinity for specific opioid receptor ligands
this theory remains controversial as each receptor is encoded by one gene
it is now theorized that alternative splicing may also be going on resulting in different opioid receptor subtypes
different opioid receptors can form heterodimers profoundly altering their signaling and pharmacology
heterodimers can increase or decrease specific opioid receptor binding or completely change the ligand affinity of the receptor
thus, if an opioid receptor forms a heterodimer or homodimer, it may have less or more affinity for an agonist an/or bind completely different ligands entirely |
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Term
| opioid receptors can form heterodimers changing their signaling |
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Definition
heterodimers of different opioid receptors can also decrease or increase GPCR coupling
opioids typically act on opioid receptors that are Gi GPCRs
however, heterodimers or homodimers of opioid receptors can alter which signaling pathway they act on
additionally, opioid receptors can form heterodimers with not only other opioid receptor subtypes, but other types of receptors such as somatostatin receptors |
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Term
therapeutic actions of opioid receptor agoninsts: analgesia
which receptors cause analgesia? |
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Definition
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Term
therapeutic actions of opioid receptor agoinsts: anti-diarrheal
which receptors cause anti-diarrheal action? |
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Definition
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Term
therapeutic actions of opioid receptor agoinsts: antitussive
which receptors cause antitussive effects? |
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Definition
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Term
| review of the spinothalamic tract |
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Definition
ascending pathway:
noxious information is received by the peripheral terminal and sent down the axon as action potentials
neurotransmitters are released (glutamate and substance P) from the central terminal of the nociceptor
these NTs act postsynaptically on 2nd order projetion neurons (in lamina I and V) resulting in action potentials
the 2nd order projection neuron projects and terminates in the thalamus releasing NTs onto the 3rd order neuron
the 3rd order neuron is depolarized and sends action potentials to the somatosensory cortex
noxious heat -> binds to TRPV1 -> increased Na and Ca -> reaches membrane threshold -> action potential -> reaches the dorsal horn (with sensory neurons) -> release of glutamate -> binds to AMPA receptors -> activation of NMDA receptors -> action potential to the thalamus -> 3rd order neurons go to the cortex |
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Term
| in the ascending pathway there are 3 possible sites opioids can produce their actions |
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Definition
peripheral terminal
synapse in spinal cord
synapse in thalamus
the result of opioid analgesic action at these sites is to block or reduce pain neurotransmission to the cerebral cortex
ALTHOUGH OPIOIDS CAN PRODUCE AN ANALGESIC EFFECT IN THE PERIPHERY, ANALGESIA PRODUCED BY OPIOIDS IS PREDOMINANTLY MEDIATED BY CENTRAL MU RECEPTORS |
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Term
| mechanism of opioid blockage of nociceptive information and processing |
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Definition
[image]
in this figure is the synapse between the primary afferent neuron terminal and the second order neuron in the spinal cord
mu opioid receptors are located pre and post synaptically
when an opioid binds to the mu receptor located in the presynaptic terminal this causes for closing of voltage gated Ca channels -> suppression of NT release (glutamate)
when opioids bind to the mu receptors located post synaptically, this causes for opening of K channels -> K efflux out of the neuron and hyperpolarization -> less nociceptive neurotransmission to the brain |
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Term
| review of the descending inhibitory pathway |
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Definition
the emotional state of a person can impact the perception of pain through activation of the descending inhibitory pathway
the descending inhibitory pathway consists of 2 different pathways
areas of the brain important in terms of emotion (such as the amygdala) have direct input into the PAG and can activate the descending system
the major role of the descedning inhibitory pathway is to selectively inhibit noxious stimuli received at the dorsal horn
periaqueductal grey (PAG) and rostral ventral medulla (RVM) pathway:
input from the amygdala comes in and activates the PAG
from the PAG it sends a neuron to the RVM
within the RVM is a particular nucleus known as the nucleus raphe magnum (NRM) which contains serotonin
neurons from the nucleus raphe magnus then send serotonergic neurons into the dorsal horn where they terminate
not all neurons coming from the RVM are serotonergic (as the NRM is just one part of the RVM) but is a major mechanism by which the RVM accomplishes descending inhibition
the serotonin is able to act on 5HT receptors to provide inhibitory feedback on the dorsal horn
the dorsal lateral pontine tegmentum (DLPT) pathway also receives input from the PAG but via a separate tract than for the RVM:
the PAG sends a neuron to the locus coereleus (LC) where it terminates
the LC is a major source of NE in the brain
from the LC another neuron projects to the spinal cord and releases NE
NE then acts on alpha2 adrenergic receptors in the spinal cord to provide inhibitory feedback on the dorsal horn
the alpha2 agonist clonidine has analgesic effects and is believed to be mediated through this pathway
NE acts on alpha2 receptors and serotonin actons on 5HT receptors to either:
inhibit release of nociceptive transmitters by acting on the central terminal of the primary afferent
OR
by inhibiting the 2nd order neuron projection neuron from relaying the nociceptive signal by acting on the receptor |
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Term
| opioids act at several sites in the descending pathway: |
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Definition
periaqueductal grey (PAG)
rostral ventral medulla (RVM)
spinal cord
administration of opioids within the PAG, RVM, and doral lateral pontine tegmentum (DLPT) can produce analgesia by binding to opioid receptors (the mu receptor is believed to be the key opioid receptor involved), resulting in activaiton of these inhibitory pathways
thus, opioids can activate the DLPT descending inhibitory pathway as well as the PAG-RVM pathway by acting at opioid receptors (mu) at these sites, leading to enhanced NE and 5HT release into the spinal cord, resulting in analgesia
opioids can also have inhibitory actions within the spinal cord |
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Term
| mechanism by which supraspinal descending neurons impact nociceptive neurotransmission in the spinal cord |
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Definition
[image]
the primary afferent has received noxious stimuli
the central terminal is the spinal cord
the central terminal will release NTs ont the 2nd order projection neuron, exciting the 2nd order neuron
1st figure:
the supraspinal neuron (from the descending inhibitory pathway) has direct inhibitory actions on the projection neuron, which will inhibit nociceptive neurotransmission
2nd figure:
the primary afferent contacts an excitatory interneurons, which then excites the projection neuron
the supraspinal neuron inhibits the excitatory interneuron to where it no longer will excite the projection neuron, decreasing nociceptive neurotransmission
3rd figure:
the primary afferent provides excitatory input to the projection neuron
the supraspinal neuron contacts the inhibitory interneurons to where the inhibitory interneuron provides inhibitory feedback onto the projection neuron, again decreasing nociceptive neurotransmission |
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Term
| mechanism of descending inhibition from NE and 5HT |
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Definition
NE and 5HT not only act on their receptors to provide inhibitory feedback into the dorsal horn, but they can also activate enkephalin containing interneurons
enkephalin is an endogenous opioid that acts on delta opioid receptors
opioid receptors are located in the dorsal horn on the central terminal of the primary afferent (presynaptically) and on the 2nd order neuron (post synaptically)
release of enkephalin can inhibit incoming nociceptive information by inhibitng voltage gated Ca channels (presynaptically - decreased Ca = decreased glutamate release) as well as by hyperpolarizing the 2nd order neuron (post synaptically) |
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Term
| several mechanisms by which opioids produce their anti-diarrheal actions |
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Definition
increase intestinal fluid absorption b/c of increased contact time
decrease intestinal fluid secretion (mediated by epithelial cells lining the crypts)
decrease GI motility |
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Term
| anti-secretory effects of opioids |
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Definition
fluid secretion is accomplished by the epithelial cells lining the crypts
in contrast, fluid absorption is accomplished by intestinal villar cells
increases in cAMP (through activation of Gs GPCRs) can induce Cl channel opening
when Cl is secreted into the lumen it generates an electochemical gradient which serves as the driving force for Na secretion through the paracellular pathway
water always follows Na leading to increased water in the lumen
thus, Cl flows into the lumen, Na follows passively, along with water
opioids produce their anti-secretory actions through peripheral mu opioid receptors
opioids bind to the mu opioid receptor, which are Gi GPCRs, decreasing cAMP, thus inhibiting Cl channel opening
since Cl channel opening is inhibited, Na stays in the blood and there is less water int he lumen of the intestine |
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Term
| mechanism of opioids decreasing GI transit |
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Definition
opioids can slow down GI transit through actions in the myenteric plexus, which regulates GI motility
peristalsis is accomplished by contraction of the circular muscle on the oral side of the bolus, with the net pressure gradient moving the food bolus caudally
the peristaltic relex is an integrated neuronal response accomplished through interactions of the enterochromaffin cells with the myenteric plexus
the enterochromaffin cells (which lines the mucosa of the gut) releases serotonin in response to chemical and mechanical stimulation
when the enterochromaffin cell releases serotonin, it binds to serotonin receptors (5HT-4) on the primary afferent neuron
binding of serotonin to the 5HT-4 receptor excites the primary afferent neuron of the myenteric plexus
the primary afferent then communicates with interneurons (through the release of NTs) which connects the primary afferent neuron (sensory input) to the motor neuron (motor output)
the motor neuron is part of the efferent component of the peristaltic response and translates sensory information into mechanical force
2 types of motor neurons: excitatory and inhibitory (the transmitter released from each type of motor neuron is different)
excitatory motor neurons release ACh to produce contraction of the circular muscles on the oral side (ACh binds to M3 receptors)
inhibitory motor neurons release NO on the anal end to produce relaxation of the circular muscle
the end result is the food bolus is moved caudally down the GI tract
there is coordinated activity between the excitatory and inhibitory motor neuron to move the food bolus down the tract
opioids act at several different sites to inhibit the peristaltic reflexes:
peripheral mu opioid receptors are found within the circular muscle layers as well as on the nerve terminal of excitatory motor neurons
opioids (such as loperamide, a peripherally acting mu opioid receptor agonist) have several different effects
1) loperamide can inhibit the excitatory motor neuron from releasing ACh by inhibiting voltage gated Ca channles
2) opioids can hyperpolarize the cirular muscle by increasing K efflux, resulting in decreased contractility
since opioids decrease the peristaltic relex, this is increased contact time for the intestinal villar cells to absorb fluid, also adding to the anti-diarrheal effects of opioids |
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Term
| opioid induced bowel dysfunction and treatment |
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Definition
major problem:
toleracne does not develop to this phenomenon
mostly associated with oral use
58% of people who took opioids regularly required more than 2 types of treatment for constipation
72% of people taking oral morphine for pain had mild to severe grads of constipation
treatment:
alvimopan - peripheral mu receptor antagonist
inhibits the actions of morphine on peripheral mu receptors from producing its anti-secretory effects and decreasing motility
in contrast, analgesia is preserved since analgesia is produced through actions of morphine on central mu receptors |
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Term
| opioid induced respiratory depression |
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Definition
mediated through mu opioid receptors
is a major drawback when using opioids in acute pain - correlates with potency of opioid
mechanism:
blockade of the respiratory regulating centers within the brain stem (pons and medulla)
lessened sensitivity to an increase in arterial pCO2, decrease in pH and/or reduction of arterial pO2 |
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Term
| mechanism of respiratory depression |
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Definition
central chemoreceptors located in the brain stem are the most important mechanism for regulating the minute to minute control of breathing
these chemoreceptors are located on the ventral surface of the medulla near the medullary inspiratory center
the medullary inspiratory center sets the frequency of inspiration
brain stem chemoreceptors are very sensitive to changes in pH of CSF
decreases in the pH of CSF produce an increase in the breathing rate (hyperventilation)
increases in the pH of CSF produce decreases in breathing rate (hypoventilation)
the medullary chemoreceptors respond directly to changes in the pH of CSF and indirectly to changes in arterial pCO2
in the blood, CO2 combines with H2O to form H+ and HCO3-; these ions are trapped in the vascular compartment and do not enter the brain (as they are ionized)
however, CO2 is permeable across the BBB and the brain CSF barrier, entering the extracellular fluid of the brain as well as the CSF
in the CSF, CO2 is converted to H+ and HCO3-
thus, increases in arterial pCO2 produce increases in pCO2 in CSF, which results in an increase in H+ concentration in CSF (decrease in pH)
the central chemoreceptors are in close proximity to CSF and detect the decreases in pH
a decrease in pH then signals the inspiratory center to increase the breathing rate (hyperventilation)
the primary mechanism of respiratory depression by opioids involves a reduction in the responsiveness of the brainstem respiratory centers to carbon dioxide (and pH)
the respiratory depressant effects are mediated by the mu opioid receptors
if a person isn't breathing enough, there is going to be an increase of CO2 in arterial blood
higher CO2 concentration is going to cross from the periphery to the brain and CSF
increase CO2 and water is going to form higher levels of carbonic acid, leading to decreased pH and bicarbonate
however, now that our opioid is present, the decreased pH is no longer going to signal the inspiratory center to stimulate increased breathing |
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Term
| respiratory depression reaches a ceiling effect with partial agonists |
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Definition
[image]
the respiratory depressant effects of opioids are mediated by the mu receptor as they depress teh sensitivity of medullary respiratory center
full agonists vs. partial agonists have a very different impact on respiratory depression
with fentanyl progressively increasing the dose progressively decreases the tidal volume leading to apnea or suspension of breathing
with buprenorhine (partial agonist at the mu receptor) increasing the dose of buprenorphine also decreases the tidal volume, but due to the fact it doesn't have the intrinsic activity of a full agonist, it can only depress respiration so much and thus reaches a "ceiling effect" |
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Term
| reinforcing effects of opioids in the mesolimbic dopamine pathway |
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Definition
opioids have reinforcing or euphoriant effects
opioids produce their reinforcing effects through activation of the mesolimbic dopamine pathway
the mesolimbic dopamine pathway is composed of the ventral tegmental area (VTA) and nucleus accumbens (nAc)
addictive substances sucha as cocain, nicotine, and opioids produce their effects by enhancing nucleus accumbens dopamine release
the reinforcing effects of opioids are predominantly due to activation of the mu receptor present within the ventral tegmental area
properties of the opioid can also influence hwo reinforcing it is
the faster it gets into the brain (and to the VTA) the more reinforcing it is
heroin is much more lipophilic than morphine to where it can get to the brain much more readily
additionally, if one uses the IV route versus the oral route, this will get the opioid to the brain much more quickly
the exact mechanism by which opioids activate the mesolimbic dopamine system is not known
opioids produce their reinforcing effects centrally through the mu opioid receptor
animals will readily self-administer mu opioid receptor agonists
in contrast, they will not self-administer kappa receptor agonists, which cause dysphoria
in general, the potency of opioids such morphine, fentanyl, and others in producing reinforcing effects is correlated with their binding affinity for central mu opioid receptors |
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Term
| reinforcing and dysphoric effects of opioids |
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Definition
the ventral tegmental area (VTA) is believed to be the site of action for the reinforceing effects of most opioids via the mu receptor
within the VTA, there is excitatory and inhibitory input
opioids act on mu receptors of GABAergic neurons
these GABAergic neurons normally have inhibitory actions on VTA dopamine neuronal cell firing. however, opioids inhibit these inhibitory GABAergic enurons, resulting in increased VTA dopamine neuronal cell firing and release of dapamine from the nucleus accumbens (resulting in reinforcement)
[image]
dynorphin is well known to produce dysphoric effects
dynorphin is believed to produce its dysphoric effects by having inhibitory actions on the mesolimbic dopamine pathway.
dynorphin is thought to act on kappa receptors present on nucleus accumbens terminals, inhibiting mesolimbic dopamine release |
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Term
| development of tolerance to opioids (for some effects) |
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Definition
a dose response curve shifts to the right. need increased amount of drug to produce the same response as before
[image] |
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Term
| tolerance does NOT develop to |
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Definition
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Term
| tolerance DOES develop to |
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Definition
euphoria
analgesia
sedation
respiratory depressant effects
nausea and vomiting |
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Term
| mechanism of tolerance (intracellular signaling) |
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Definition
tolerance develops: increased adenylyl cylase, increased cAMP
[image]
this mechanism is fairly specific to opioids as the tolerance to the effects of opioids correlates with the cAMP intracellular signaling system
in a person with no drug, there is a certain level of cAMP generation
opioid receptors are linked to Gi subtype of GPCR which inhibits adenylyl cyclase (the enzyme that converts ATP to cAMP)
if you give a person morphine, morphine results in a drop in cAMP levels with no effect on adenylyl cyclase
with continued administration of morphine, adenylyl cyclase and cAMP levels rise (this return of cAMP levels toward baseline correlates with development of physical dependence.
when morphine is discontinued there is a sharp spike in cAMP levels, with the spike in cAMP levels above baseline correlating well with withdrawal symptoms
with discontinuation of morphine, recovery from withdrawal correlates with return in cAMP levels to baseline
one withdrawal effect is diarrhea
withdrawal = increased cAMP
increased cAMP will increase Cl channel opening, resulting in higher Cl in the lumen of the intestine, Na follows the Cl along with water
the absorptive capacities are overwhelmed and too much fluid is presented to the colon, resulting in diarrhea |
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Term
| symptoms of opioid withdrawal |
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Definition
runny nose
lacrimation
diarrhea
piloerection (goosebumps)
restlessness and insomnia
pain and irritability
flu-like syndrome |
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Term
| time course of opioid withdrawal syndrome |
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Definition
depends on the t1/2 of the drug
methadone has a long t1/2; causes months of withdrawal symptoms
also depends on:
dose
frequency of administration
duration of drug use |
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Term
| what is opioid induced hyperalgesia? |
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Definition
a paradoxical response to opioid agonists resulting in an increased perception of pain rather than an antinociceptive effect
characteristics:
increased sensitivity to painful stimuli
worsening pain despite increasing doses of opioids
pain that becomes more diffuse, and pain that extends beyond the distribution of preexisting pain |
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Term
| examples of opioid induced hyperalgesia |
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Definition
| sustained opioid infusion can result in mechanical allodynia and thermal hyperalgesia |
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Term
| mechanism of opioid induced hyperalgesia |
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Definition
sustain opioid infusion can increase spinal dynorphin
dynorphin levels in the spinal cord was significantly higher in groups with the active oxymorphone than in groups with the inactive oxymorphone
this results suggests that the increase in dynorphin in the spinal cord may be responsible for the mechanical allodynia and thermal hyperalgesia following sustained opioid exposure
to determine if the increased dynorphin in the spinal cord was responsible for the mechanical allodynia and thermal hyperalgeia, rats were infused with either saline, DAMGO (mu receptor agonist), or DAMGO + dynorphin antiserum
the DAMGO infusion resulted in decreased paw withdrawal thresholds
shows that chronic administration of a mu receptor agonist can cause mechanical allodynia and thermal hyperalgesia
adminstration of dynorphin antiserum with DAMGO resulted in restoration of normal mechanical thresholds
suggests that perhaps dynorphin antiserum restored the analgesic efficacy of DAMGO |
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