Pain System 2 Flashcards
What does damaged tissue or inflammation release?
NGF, bradykinin, serotonin, ATP, histamine, prostaglandins, H+, K+, cytokines (IL6 and IL1beta, TNFalpha)
(inflammatory soup)
Describe how the chemical sensitization of nociceptors occurs.
- damaged tissue or inflammation releases inflammatory soup
- inflammatory soup sensitizes the nociceptor
- nociceptor releases CGRP and Substance P
- vasodilation occurs
“backwards release” (ask someone to explain)
What are TRP channels?
variety of ligand gated ion channels activated at different temperatures
What kind of neurons can TRPV1 be found on? What are they activated by? At what temperature are they activated?
- on small nociceptive neurons
- activated by: capsaicin, moderate thermal stimuli, H+ ions
- temperature: 43 degrees celcius
Which channels do chili peppers activate?
TRPV1
What kind of neurons can TRPV2 be found on? What are they activated by (temperature) ?
- on A-delta cells (to lamina I)
- activated by intense noxious heat >52 degree celcius
At what temperature are TRPM8 receptors activated? What are they activated by?
- cold/cool temperatures –> 8-22 degree celcius
- activated by menthol and icilin
Which substance increases sensitivity of all TRP channels?
bradykinin
label the diagram on slide 7.
flare, mechanical hyperalgesia
When inflammatory factors are release at an injury, an area of ____________________ develops around the original injury.
hyperalgesia
excitation of which type of pain fiber causes release of substance P and CGRP? Where are they released from?
- C-fiber
- released from sensory nerve endings
What are the effects of the release of substance P and CGRP?
- excite other C-fibers
- axon reflex
- vasodilation (redness)
- extravasation of plasma proteins (add to inflammatory soup)
- oedema (swelling)
- migraine pain
Provide an overview on how neurogenic inflammation can cause sensitization of sensory nerve fibers.
DETAILS:
- prostaglandin sensitizes TRP channels via PKA –> phosphorylate Na+ channel –> TRP channel open at lower temperature threshold –> generate more APs
- bradykinin sensitizes TRP channels –> reduce threshold for activation –> increased output to a given stimulus
OVERVIEW:
1. CGRP and substance P stimulate mast cell
2. mast cell release histamine
3. bradykinin and prostaglandin sensitize the axon
4. axon further releases CGRP and substance P to stimulate blood vessel
If pain signals tissue damage, why do we have endogenous analgesic mechanisms? What substance play a role in the analgesia?
- central mechanisms that suppress pain have a significant survival value
- endogenous opioids (enkephalin, dynorphin, endorphin, endomorphin) dampen pain signals
Where are pain signals modified in the descending top down inhibitory pain path?
- PAG
- RVM
What mechanism hold the descending analgesic pathways in check so that we can feel pain?
tonic GABAergic inhibition in RVM and PAG
draw the descending analgesic pathway from amygdala to spinal opioid INs.
slide 12
What is the prototypical substance for analgesia
opioids
What are the 3 endogenous opioids? What are the 3 pro-hormones?
- endogenous opioids: endorphin, dynorphin, enkephalin
- pro-hormones: POMC, prodynorphin, proenkephalin
What are the 3 MAIN endogenous opioid receptor types?
mu, kappa, delta
What were the initial opioid receptor types identified?
mu, kappa, sigma
Which opioid receptor type is bound by enkephalins? endorphins?
- delta bound by enkephalins
- epsilon bound by endorphins
What is the mechanism of action of opioid receptors?
- GPCR
- inhibit adenylyl cyclase
- open K+ channels
- hyperpolarization
Which opioid receptor is most widely expressed?
mu opioid receptors
What is the main action of mu1 vs mu2 receptors? peripheral or spinal/supraspinal?
- mu1: analgesia (peripheral and spinal/supraspinal)
- mu2: respiratory depression, bradycardia, euphoria, ileus (spinal/supraspinal)
What does binding of the kappa opioid receptor produce? peripheral or spinal/supraspinal? Which effects are negative?
- analgesia
- sedation
- dysphoria (negative)
- psychomimetic effects (negative)
- inhibit ADH release (promote diuresis) (negative)
- peripheral and spinal/supraspinal
What is the function of delta opioid receptors?
- potentiate effects of both mu1 and mu2
- analgesia and undesirable effects
TRUE or FALSE: it is thought that mu and kappa receptors exist together as a complex
FALSE: mu and delta
TRUE or FALSE: ketamine is an opioid
FALSE: anesthetic induction agent that possesses analgesic properties
How does ketamine affect the sympathetic nervous system?
- activate sympathetic nervous system
- maintain blood pressure and heart rate; bronchodilation
What is ketamine a derivative of?
phencyclidine derivative (PCP, angel dust)
What kind of anesthesia does ketamine produce?
dissociative anesthesia
what kind of state does ketamine resemble?
cataleptic state
What are the mechanisms of action of ketamine? Where does it bind?
- binds non-competitively to PCP recognition site on NMDARs –> blocks NMDARs (KEY)
- effects on opioid receptors
- monoaminergic receptors –> voltage-gated Na+ channels
How does ketamine affect NMDARs
ketamine binds a site in the channel pore (acts similar to Mg2+ ion) to block conductance through channel (Ca2+)
note: even if Mg2+ block removed from NMDAR, if ketamine still present, ions still cannot flow through
What is the action of NSAIDs in analgesia? does it act centrally or peripherally? When is the best time to use it in terms of surgery?
- block prostaglandin synthesis –> take away sensitization (decrease hyperactivity)
- central and peripheral
- best if used pre- or perioperatively
What is the pro and con of NSAIDs in comparison to opioids?
- pro: not as dangerous as opioids bc no respiratory depression
- con: inhibition is not as direct
classify the following as acting centrally or peripherally:
- NSAIDs
- mu1
- mu2
- kappa
- NSAIDs = central and peripheral
- mu1 = central and peripheral
- mu2 = central
- kappa = central and peripheral
(check notes again)
