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Pain - Sandoval 2

Additional Pharmacology Flashcards




endogenous opioid peptides



what receptors do the endogenous opioids (endorphins, endomorphins, dynorphins, and enkephalins) bind to?
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
generation of endogenous opioids
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
generation of endorphins (stress and synthesis of endorphins)
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
runner's high, an opioid link?
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
generation of enkephalins
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
generation of dynorphins
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
affinity of dynorphin analogs for kappa receptors
Dyn A 1-17 > big-Dyn = Dyn B = Dyn B 1-29 = alpha-neo-endorphin > Dyn A 1-8 = beta-neo-endorphin


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
dynorphin and neuropathic pain
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
mechanism of L5/L6 nerve ligation resulting in mechanical allodynia and thermal hyperalgesia
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
dynorphin levels after L5/L6 nerve ligation
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
it is suggested that dynorphin A 1-17 is elevated following nerve ligation, what happens if dynorphin is administered?
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
NMDA receptor antagonists can block the effects of dynorphin
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
effect of dynorphin antiserum on mechanical allodynia and thermal hyperalgesia
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
most endogenous opioids share a common NH2 sequence except:

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
opioid receptors
important pharmacological effects mediated by the mu opioid receptors and location
analgesia (central)
euphoria (central)
respiratory depression
anti-diarrheal effects (peripheral)

localization of receptors:
periaquaductal gray
spinal cord
enteric smooth muscle
important pharmacological effects mediated by delta opioid receptors and location

localization of receptors:
spinal cord
important pharmacological effects mediated by kappa opioid receptors and location
dysphoria (central)

localization of receptors:
spinal cord
receptor activity of agonists opioid drugs

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
receptor activity of mixed opioid receptor agonists

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
receptor activity of opioid receptor antagonists

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)
opioid differ in their potency.

potency is influenced by:
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


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
MOA of opioids
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
mu opioid receptor subtypes
mu1 and mu2 receptors

mu1 and mu2 receptors both mediate analgesia

only m2 mediates respiratory depression and constipation
opioid receptors can form heterodimers altering their pharmacological properties
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
opioid receptors can form heterodimers changing their signaling
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
therapeutic actions of opioid receptor agoninsts: analgesia
which receptors cause analgesia?
therapeutic actions of opioid receptor agoinsts: anti-diarrheal
which receptors cause anti-diarrheal action?
therapeutic actions of opioid receptor agoinsts: antitussive
which receptors cause antitussive effects?
review of the spinothalamic tract
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
in the ascending pathway there are 3 possible sites opioids can produce their actions
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

mechanism of opioid blockage of nociceptive information and processing

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
review of the descending inhibitory pathway
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
by inhibiting the 2nd order neuron projection neuron from relaying the nociceptive signal by acting on the receptor
opioids act at several sites in the descending pathway:
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
mechanism by which supraspinal descending neurons impact nociceptive neurotransmission in the spinal cord

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
mechanism of descending inhibition from NE and 5HT
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)
several mechanisms by which opioids produce their anti-diarrheal actions
increase intestinal fluid absorption b/c of increased contact time

decrease intestinal fluid secretion (mediated by epithelial cells lining the crypts)

decrease GI motility
anti-secretory effects of opioids
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
mechanism of opioids decreasing GI transit
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
opioid induced bowel dysfunction and treatment
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

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
opioid induced respiratory depression
mediated through mu opioid receptors

is a major drawback when using opioids in acute pain - correlates with potency of opioid

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
mechanism of respiratory depression
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
respiratory depression reaches a ceiling effect with partial agonists

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"
reinforcing effects of opioids in the mesolimbic dopamine pathway
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
reinforcing and dysphoric effects of opioids
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)


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
development of tolerance to opioids (for some effects)
a dose response curve shifts to the right. need increased amount of drug to produce the same response as before

tolerance does NOT develop to

tolerance DOES develop to
respiratory depressant effects
nausea and vomiting
mechanism of tolerance (intracellular signaling)
tolerance develops: increased adenylyl cylase, increased cAMP


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
symptoms of opioid withdrawal
runny nose
piloerection (goosebumps)
restlessness and insomnia
pain and irritability
flu-like syndrome
time course of opioid withdrawal syndrome
depends on the t1/2 of the drug

methadone has a long t1/2; causes months of withdrawal symptoms

also depends on:
frequency of administration
duration of drug use
what is opioid induced hyperalgesia?
a paradoxical response to opioid agonists resulting in an increased perception of pain rather than an antinociceptive effect


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
examples of opioid induced hyperalgesia
sustained opioid infusion can result in mechanical allodynia and thermal hyperalgesia
mechanism of opioid induced hyperalgesia
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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