Term
|
Definition
| SOMATIC PAIN: sharp, intense, mediated by fast A-delta fibers which enter the spinal column at the dorsal horn. |
|
|
Term
|
Definition
| VISCERAL PAIN: diffuse, poorly localized, mediated by slow C fibers, which enter the spinal cord at the dorsal horn. |
|
|
Term
| What type of pain is alleviated by opioids? |
|
Definition
| Both types of pain are alleviated by opioids. |
|
|
Term
| what does an opioid analgesic do for relief of pain? |
|
Definition
OPIOID ANALGESIC: “It hurts but who cares?” Due to inhibition of pain perception, primarily in cortical and subcortical brain, and euphoria.
THIS IS VERSUS:
LOCAL ANESTHETIC: “It doesn’t hurt anymore. It’s numb.” Due to inhibition of axonal conduction. Prototype drug is cocaine. Local (peripheral) interference with sending pain signals to the CNS. |
|
|
Term
| What are the CNS effects? |
|
Definition
| CNS: analgesia, euphoria (dysphoria), sedation, respiratory depression, release of prolactin, nausea, anti-tussive effect |
|
|
Term
|
Definition
| C-V: peripheral vasodilation |
|
|
Term
| What are the eye effects? |
|
Definition
EYE: pupillary constriction
pasms. |
|
|
Term
| What are the lung effects? |
|
Definition
| LUNGS: respiratory depression |
|
|
Term
|
Definition
| GI: decrease in propulsive contractions in the small intestine and colon. Spasms |
|
|
Term
| What are the pharmakinetics? |
|
Definition
Onset of morphine action is rapid after IV (< 1 min) or IM (10 min); onset is slower (30 min) after oral intake.
Morphine’s duration of action is 3-4 hrs. |
|
|
Term
| What is morphine's primarly metabolic route for metabolism? |
|
Definition
| Glucuronide conjugation (first-pass metabolism) in liver is primary metabolic route for morphine. 90% of morphine is excreted in urine as the glucuronide within 24 hrs. |
|
|
Term
| what is spinal analgesia? |
|
Definition
| Opioid analgesia has spinal (minor) and supra-spinal components. MU receptors mediate both spinal (DRG) & supra-spinal analgesia in periaquaductal grey matter, thalamus, sensory cortex. Delta receptors also mediate spinal analgesia for pain C fibers in the spinothalamic tracts. These receptors are located in the dorsal horn of the spinal cord. |
|
|
Term
| what happens in the peri-aquaductal grey? |
|
Definition
| this is where neurons origniate in a descending pain control pathway, which has a synapse in the nucleus raphe magnus, then terminates in the dorsal horn. It is the dorsal horn where pain impulses are inhibited. |
|
|
Term
| what activates peri-aquaductal grey neurons? |
|
Definition
|
|
Term
| what is supraspinal analgesia? |
|
Definition
| inhibition of pain impulses of the peri-aquaductal grey by MOR agonists |
|
|
Term
|
Definition
|
|
Term
| How does morphine produce analgesia? |
|
Definition
| by binding to the MOR in the CNS |
|
|
Term
| where does supraspinal analgesia occur? |
|
Definition
| in the periaquaductal grey |
|
|
Term
| what is spinal analgesia mediated through? |
|
Definition
| delta and kappa opioid receptors |
|
|
Term
| How are the euphoric (rewarding) properties of morphine produced? |
|
Definition
| Through binding to MOR receptors in the ventral tegmental area (VTA), nucleus accumbens, and medial prefrontal cortex. Morphine (and EtOH, cocaine, food, sex) increase Dopamine release from these VTA nerve terminals, in the nucleus accumbens, and medial prefrontal cortex. This increased dopamine release in the nucleus accumbens and medial prefrontal cortex is an essential component of the brain reward system. |
|
|
Term
| where is nausea produced? |
|
Definition
|
|
Term
| Where is respiratory depression produced? |
|
Definition
| in the brainstem. This decreases neuronal sensitivity to P(CO2) (the cause of death in OD), |
|
|
Term
| What is the cause od death in an opioid OD? |
|
Definition
|
|
Term
| Where are anti-tussive action produced? |
|
Definition
| in the brainstem (d-isomers and l-isomers are equally toxic!) |
|
|
Term
| where are Mu opioid receptors found? |
|
Definition
| medial prefrontal cortex, nuc accumbens, and ventral tegmental area |
|
|
Term
| Are the mu receptors involved in the euphroria response or the analgesic response? |
|
Definition
| both. We can't seem to tease the euphoric and analgesic response apart. |
|
|
Term
| how does an opiod work on a cellular level? |
|
Definition
heroin binds to a mu opioid receptor on a gabaergic interneuron that normally inhibits a dopamine interneuron. By this mechanism, heroin will inhibit the inhibitory gabaergic neuron, allowing dopanergic neurons to freely fire. When this neuron enters burst firing mode, that is the essential electo-physiological signal of REWARD in the brain. By this mechanism, enormous amounts of dopamine are released, and we think something great is happening.
Also, opiod receptors are found inhibiting postsynaptic activing. This also contributes to euphoria and the block of pain perception. When an MOR agonist binds to its receptor, the Gi alpha subunit of the GTP binding protein inhibits adenyl cyclase, leading to a decrease in cAMP levels. The decreased cAMP levels leads to a decrease in protein kinase A--> which leads to decreased cAMP response element binding protein (CREB). This results in braod changes in gene expression. In addition, K+ are allowed to flow into the cell through inwardly-rectifying channels, resulting in HYPERpolarization. |
|
|
Term
|
Definition
| GI: Decreased propulsion (constipation) in intestines is produced by actions at the local gut ganglia. |
|
|
Term
|
Definition
| EYE: Constriction of the pupil is produced by actions at the nucleus of the 3rd cranial nerve (oculomotor). |
|
|
Term
|
Definition
| C-V: Peripheral vaso-dilation is produced by action at the vagal nucleus. |
|
|
Term
| what are the 3 main endogenous opioid receptor ligands in the CNS? |
|
Definition
| endorphin, enkephalin and dynorphin |
|
|
Term
| what are the 3 main receptor subtypes? |
|
Definition
There are 3 main opioid receptor subtypes: mu, delta and kappa. All are G-protein coupled…
MU and DELTA bind enkephalins and endorphins preferentially
KAPPA binds DYNORPHIN |
|
|
Term
| Which receptor does morphine use most of the time? |
|
Definition
| MU opioid receptor (OPRM1, on 6p24) mediates most of the rewarding and analgesic effects of morphine. |
|
|
Term
|
Definition
| MU agonists increase outward flux of K ions, hyperpolarizing neurons. MU agonists also decrease cAMP production. The endogenous opioids, endorphin and enkephalin, preferentially bind to the MU opioid receptor. |
|
|
Term
| describe the acute cellular response to morphine: |
|
Definition
| Morphine (opioid agonist) binds. cAMP decreases, decrease protein kinase A,, producing a host of transcriptional changes, which are mediated through CREB phosphorylation (so this decreases). Within 30 minutes of admin of a Mu agonst, you have profound changes in transcription of 100s of genes. This leads to altered gene expression, and acute adaptations to morphine. The END RESULT is reduced excitability (reduced transmission) at GABA/ GLU interneurons in the VTA, allowing euphorogenic, dopanergic neurons free reign to fire more freely. In addition, this results in subsequent reduction in firing, adenylyl cyclase inhibition, and neuronal hyperpolarization thru opening of K+ channels. |
|
|
Term
| what does the delta opiod receptor do? |
|
Definition
| it is a 7 transmembrane G protein that mediates a minor component of the spinal analgesic response in the dorsal horn. It binds endorphin and enkephalins preferentially. |
|
|
Term
| What does Kappa opioid receptor do? |
|
Definition
| Kappa opioid receptor (OPRK1) is on chr 8q11.2 & modulates visceral nociception (in the dorsal horn). It binds dynorphins preferentially. |
|
|
Term
| what are opiod antagonists used for? |
|
Definition
Highly specific opioid antagonists are
used for reversal of mu opioid agonist overdose. Naloxone is the prototype drug. It is administered IV (being inactive orally), and has a very rapid onset, lasting several hours. Naltrexone is a longer-acting (~48 hours) oral antagonist |
|
|
Term
| name 2 opioid antagonists |
|
Definition
|
|
Term
| what are 2 types of tolerance? |
|
Definition
Pharmacokinetic tolerance: Change in drug metabolism;; AND
Pharmacodynamic tolerance: Change in cellular response to the drug |
|
|
Term
| what are opioid withdrawl symptoms? |
|
Definition
Symptoms are mild and are
the OPPOSITE of those produced by morphine:
Anxiety instead of euphoria;
Agitation instead of sedation;
Diarrhea instead of constipation;
Pupillary dilation instead of constriction;
Accompanying these withdrawal symptoms is an
intense desire for an opioid---craving
This craving is nearly irresistible, and can be cued
by drug-related perceptions: seeing places, things
and people associated with opioid use. |
|
|
Term
| What are the possible mechanisms of opioid tolerance? |
|
Definition
mu receptor down-regulation, internalizaion and/or uncoupling from effectors.
May also involve expression of transcription factors (eg, chronic fras) which possibly
regulate synaptic remodelling processes. |
|
|
Term
| is nalaxone active orally? |
|
Definition
|
|
Term
| What is the chronic response to adaptation to morphine? |
|
Definition
| A decoupling of the mu opiod receptor from its Gi 2nd messanger system, leading to upregulation of cAMP (in contrast to acute situation), more increases of protien Kinase A, increase in phospholated CREB, and altered gene expression, Ultimately, this leads to a decrease in levels of inhibitory G proteins, a decoupling of the G protein (opiate bidning no longer inhibits adenylyl cyclase or other second messangers, and with chronic inhibition of adenyly cyclase by morphine, the cAMP generating system is upregulated. therefore, there is increased excitability through increased PKA (increasing NA inward current) , and increased neurotransmitter release. |
|
|
Term
| What is methadone maintenance? |
|
Definition
Methadone maintenance (mm): opioid dependent persons go to a clinic daily to obtain the drug. Compared to drug-free rehab, mm has 3 advantages:
Lowers rate of HIV & hepatitis;
Lowers rate of re-arrest;
Increases employment rates |
|
|
Term
| What does a buprenorphine-naloxone combination do? |
|
Definition
buprenorphine is an orally-active partial mu agonist which dissociates very slowly from the mu opioid receptor, causing less severe withdrawal symptoms.
and naloxone prevents injection |
|
|
Term
| what does naltrexone treatment for EtOH dependance do? |
|
Definition
Naltrexone (NTX) is a mu opioid receptor antagonist, useful in reducing the risk for relapse to heavy drinking (defined as > 4 drinks in 24 hours) when the drug is given with sobriety counseling.
It reduces the euphoria from ethanol, and thereby reduces the drive to drink excessively.
It has no effect on abstinence rates! |
|
|
Term
|
Definition
Mu Opioid Receptor Interacting Proteins.
These proteins bind to the mu opioid receptors, mediating receptor desensitization, down-regulating, internalization, re-insertion into membrane or degradation.
G-protein Receptor Kinase 2, Periplakin, Filamin A, Protein Kinase C Interactor 1 |
|
|
Term
| Where is euphoria produced? |
|
Definition
| VTA to NA and medial prefrontal cortex |
|
|
Term
| Where is nausea produced? |
|
Definition
|
|
Term
| Where is respiratory depression caused? |
|
Definition
| Brain stem (this is cause of death in OD) |
|
|
Term
| Where is anti-tussive action produced? |
|
Definition
|
|
Term
| What is supraspinal analgesia? |
|
Definition
MOR agonists activate neurons in the periaqueductal gray, thal, and sensory cortex that terminate in the dorsal horn, where pain is inhibited.
It is a normal upregulation of the "descending modulation" of pain. |
|
|
Term
| How do opiates work to produce euphoria? |
|
Definition
| They bind onto opioid receptors (mu, kappa, or delta) which are on a GABAnergic neuron that normally inhibits dopaminergic neurons. It will inhibit the inhibitor, allowing dopamine to be released at will! |
|
|
