Opiod Receptors and Endogenous peptides Flashcards
Four broad classes of opiod receptors are currently accepted.
Most clinically important pharmacologic effects of opiod alkaloids are mediated by which receptors?
μ, κ, and δ receptors
The 4th receptors is called the nociception-orphanin FQ (NOP) receptor - may also be invovled in pain processing
Which receptors mediate the classic classical pharmacological effects of morphine?
What are these classical effects of morphine
μ receptors
The classic effects are analgesia and ventilatory depression
There are many subclasses of μ receptors and what do they mediate
μ1 - supraspinal analgesia
μ2 - ventilatory depression and spinal analgesia
μ3 - vascular control and immune modulation (on leukocytes)
Although genetic polymorphisms exist, most receptor variants are a result of posttranscriptional or posttranslational modifications
μ receptors are encoded by which gene?
What explains the variability seen in how patients respond to opiods
OPRM1, found on Chr 6q24-q25.
Although genetic polymorphisms exist, most receptor variants arise from posttranscriptional or posttranslational modifications. The transcribed
mRNA may be modified by splicing or polyadenylation, whereas the receptor may be covalently modified by phosphorylation or conjugation to ubiquitin.
More than 20 μ-receptor variants have been identified and cloned. This heterogeneity explains.
- Why opioids have variable efficacy and toxicity in different patients
- It may also account for the fact that patients who are tolerant to the effects of one μ agonist can sometimes get relief with another.
Which opiod receptors is responsible for the dysphoria effect of opiods?
The κ receptors
- These receptors are encoded by a single gene but can theoretically produce at least 6 mRNA variants
Which κ receptors respond to analgesics that are used clinically and what are their effects?
κ1 receptor - spinal analgesia
κ3 receptor - supraspinal analgesia, sedation, and
ventilatory depression
What is the most prevalent opiod receptor in the brain and what does it do?
κ3 receptor which results in supraspinal analgesia, sedation, and ventilatory depression
Which receptor is responsible for mediating some of the analgesic effects of endogenous opiod peptides, especiall in the spinal cord?
δ receptor
Only a few clinically opiods have affinity for this receptor at usual analgesic doses
If a μ-selective opioid is administered in a sufficiently high dose (to treat a tolerant patient, for example), the drug may be less selective and produce significant δ effects
What kind of receptors are opiod receptors?
These are G-protein couple receptors
-All have 7 transmembrane domains and significant structural homology
What is the overal action of actions of both μ and δ agonists?
They result in overal neuronal depression
They share several signal transduction
mechanisms, including:
- Inhibition of adenylyl cyclase,
- Activation of K+ currents - hyperpolarizes postsynaptic neuronal membranes and reduce their responsiveness
- Suppression of Ca2+ currents - this prevents the release of neurotransmitters involved in pain like Substance P in the pre-synaptic cell
Other mechanisms have been demonstrated, including stimulation of phospholipase C and mitogen-activated protein kinase, as well as blockade of calcium channels. The κ receptor elicits similar cellular responses, and it may also block calcium channels.
What are the five families of endogenous opiods?
EPPPE - 5 of them
Enkephalins
Dynorphins
Beta-endorphin (most important)
Orphanin FQ
Endomorphins
What are enkephalins?
What are they derived from?
What opiod receptor are they selective for?
Where are enkephalins found?
These are endogenous peptides derived from proenkephalin A
Selective for δ receptors
Act as neurotransmitters released from short interneurons within the spinal cord and brainstem.
They are found in the adrenal medulla and in nerve
terminals that contain catecholamines.
What is the structure of proenkephalin A (the molecule that gives rise to enkephalins)?
Each molecule of proenkephalin contains:
- Four sequences of met-enkephalin (Tyr-Gly-Gly-Phe-Met),
- One copy of leu-enkephalin (Tyr-Gly-Gly-Phe-Leu)
- Some slightly larger enkephalin-like peptides
What is the enkephalins mechanism of action?
Enkephalins (and exogenous opioids) bind to presynaptic opioid receptors on nociceptive neurons and modulate the release of various pain neurotransmitters.
The naturally occurring enkephalins are hydrolyzed extremely rapidly by peptidases in plasma. Stable analogues of the enkephalins have been synthesized, permitting in vivo experiments on their actions.
What are dynophins and what are they derived from?
Which receptors are they selective for?
Where are they found?
These are endogenous opiods. There is dynorphin A and B both from Prodynorphin (aka proenkephalin B)
Dynorphins show selectivity for the κ receptor
Just like enkephalins - They are found in the adrenal medulla and in nerve
terminals that contain catecholamines.
The 5 amino acids at the N-terminus
of the dynorphins are identical in sequence to leu-enkephalin.
What is propriomelanocortin (POMC)?
Where is it found?
What important opiod does it form (what receptor does this opiod affect)
Selectve cleavage of POMC can also give what hormones?
It is a protein that contains a multitude of opiod and nonopiod peptides
It is found in high concentration in the anterior pituitary and the hypothalamus
Side note: The N-terminus of POMC is identical to met-enkephalin, although POMC is not cleaved to yield met-enkephalin.
β-endorphin (formed from the final 31 amino acids) - is the most important of the humoral endogenous opioids, and an important endogenous ligand at the μ receptor.
Selective cleavage of POMC yields many nonopioid hormones including:
- Adrenocorticotropic hormone (ACTH),
- Several varieties of melanocyte stimulating hormone (MSH),
- Lipotropins.
What is orphanin FQ aka nociceptin
Why is it the orphan?
What is its mechanism of action?
Where is it found in the body?
What are its effects?
This is a peptide containing 17 amino acids derived from the cleavage of Proorpphanin
Although proorphanin has significant sequence
homology with the other 3 parent opioid peptides, orphanin FQ does not bind to μ, κ, or δ receptors –> it is the orphan of the endogenous opiods.
Mechanism: It binds to a G-protein coupled receptor (NOP) and causes cellular responses similar to other opioids, including inhibition of adenylyl cyclase, opening of the inwardly rectifying potassium channel, and blockade of calcium channels.
Found in the hippocampus and sensory cortex
Effects
- Supraspinal antianalgesic effect while producing spinal analgesia
What are endomorphins
What are the types and the receptors they affect?
What are the cardiovascular effects (centrally and peripherally)
They are endogenous agonists that have high affinity and high selectivity for the μ receptor.
A precursor molecule for the endomorphins has not yet been identified.
- The tetrapeptide Tyr-Pro-Trp-Phe-NH2 is called **endomorphin-1 ** –> acts via stimulation of μ2 receptors
- peptide, Tyr-Pro-Phe-Phe-NH2, is called endomorphin-2 –> less specific, acting at both μ and κ receptors.
These peptides have both in vitro and in vivo cardiovascular effects:
- They decrease spontaneous neuronal discharge in the rostral ventrolateral medulla (RVLM), an area important in the central control of blood pressure.
- Peripherally, they decrease norepinephrine release from vascular sympathetic neurons.
What is the physiological role of morphine:
Immunomodulatory or Analgesic?
The physiologic role of morphine is more likely to be immunomudulatory
Mammals have the ability to synthesize morphine from tyrosine precursors, using the same reaction scheme as the opium poppy. The significance of
endogenous morphine is unknown, but it is interesting that arthritic rats make more morphine than do healthy ones. The concentration of endogenous morphine is too low to activate μ1 or μ2 receptors, but its concentration is within the range that activates μ3 receptors on lymphocytes. This finding indicates that its physiologic role is more likely to be an immunomodulator rather than an analgesic.
What was the described role of COX-1
What are the major roles of prostaglandins made from COX-1
COX-1 role
- platelet adhesiveness
- protection of the gastrointestinal tract against damage from acid
These are expressed in most tissues
Prostaglandins made from COX-1 major roles:
- nociception
- GI mucosal intergrity
- glomerular filtration rate
- platelet TXA2 synthesis
