Pain, nociception and analgesia Flashcards
What is the definition of Pain?
The subjective conscious appreciation of a stimulus that is causing, or threatening to, cause tissue damage
What is the definition of Nociception?
The physical process of detection and transmission of a noxious stimuli
What are nociceptors?
They detect noxious stimuli
What is the definition of analgesia?
Reduction or prevention of either nociception or pain (without loss of consciousness)
What do mechanical nociceptors detect?
High intensity mechanical Strong thermal (>60C)
What do polymodal nociceptors detect?
High intensity mechanical
Thermal (>45C and <10C)
Chemical
The A(delta) fiber is responsible for what sort of pain?
Fast pain
Sharp, pricking
Well-tolerated
The C fiber is responsible for what sort of pain?
Slow pain
Burning, aching, throbbing,
Poorly tolerated
Which fibers are myolenated? A(delta) or C?
A(delta)
This means they transmit signals quicker
Which fibers have a larger diameter? A(delta) or C?
A(delta)
ASIC (Acid sensing ion channels) detect what?
Acid (H+)
P2X3 (Purinergic receptor) detects what?
ATP and Mechanical stimulation
VGNa (Voltage gated sodium ion channel) detects what?
Mechanical stimulation
VR-1/TRPV-1 (Vanilloid -1 receptor) detects what?
Capsaicin
H+
Heat
Is nociception just exaggerated sensory transmission?
They conduct at slow velocities
Nociceptors have different thresholds of activation
They have different sites of projection into the spinal cord
They elicit different physiological responses in dorsal horn neurones
Information ascends in different pathways
Nociceptors detect what in relation to heat?
Intensity
Thermoreceptors detect what in relation to heat?
Presence (not intensity)
Which neurone(s) synapse to the wide dynamic range neurone?
A(delta) fibre only
Which neurone(s) synapse to nociceptive neurones
Both A(delta) and C fibres
Spinothalamic pathway
Cerebral cortex
Thalamus
Lateral spinothalamic tract
Dorsal root axon (A(d), C)
Responsible for pain, temperature and some touch
Dorsal column - medial lemniscal pathway
Cerebral cortex Thalamus Medial lemniscus Dorsal column Dorsal root axon (A(a), A(b), A(d)
Responsible for touch, vibration, two point discrimination, proprioception
What is referred pain?
When two fibres synapse to the same neurone
What is hyperalgesia?
Increased response to a noxious stimulus
What is Allodynia?
Painful responses to non-noxious stimulus
What is neuropathic pain?
Pain unrelated to peripheral nociception, sometimes called pathological pain (serves no purpose)
e.g nerve damage, spinal damage, thalamic stroke
What is an itch?
Afferent input is via both A(d) and C fibres from free nerve endings.
Inflammation can cause it
However, analgesics don’t inhibit itch!
Do analgesics inhibit itch?
No
What are the differences between A(d) and C fibres PREsynaptically?
C fibre terminals contain more substance p (cgrp)
What are the differences between A(d) and C fibres POSTsynaptically?
Both A(d) and C fibres synapse to AMPA and NMDA receptors
But only C fibres synapse to NK-1 receptors
Substance P activates what?
Gq GPCR (increased Na/Ca influx, decreased K efflux, increased IP3)
TRUE/FALSE? Nociceptor transmission can undergo ‘wind-up’
TRUE
What chemical inhibits ‘wind-up’
2-AP5
A(a) and A(b) non-nociceptive mechanoceptors do what in relation to the C-fibre?
They inhibit the C-fibre
What is supraspinal control of pain?
Brain stimulation inhibits nociceptive spinal neurones (causes pain relief)
Describe the descending pain pathway
Hypothalamus
PAG (Midbrain)
Raphe Nuclei (Medulla)
Dorsal Horn (Spinal Cord)
Describe the action of Opioids (in terms of brain regions)
Excite/Increase:
- PAG
- Nucleus reticulas (medulla) - excites raphe nuclei
Inhibit:
- Dorsal horn/Spinal cord
- Periphery
What is the action of opioids in the PAG
Inhibit both glutamate and GABA release
But glutamate is released from multiple neurones so leads to an overall increase in excitation of the raphe nuclei (medulla).
How do opioids inhibit the dorsal horn?
Decrease signals from primary afferent neurone and decrease signals coming from PAG + locus coeruleus
Overall decrease in excitation of second order projection neurone
What are the endogenous opioid peptides?
B-Endorphin Enkephalins (Met and Leu) Dynorphin A(1-17)
How do enkephalins work? (in terms of receptors)
Activate Gi GPCRs
Leads to decreased Ca influx and increased K efflux
Inhibits production of PKA
U-opioid receptors target which site(s) of analgesia?
Supraspinal
Spinal
Peripheral
K-opioid receptors target which site(s) of analgesia?
Spinal
Peripheral
Delta-opioid receptors target which site(s) of analgesia?
Spinal
The descending pain pathway does what?
Decreases nociception
How do opiates work?
Act on opioid receptors
mimic endogenous opioids
Opioid receptors activate which type of channel?
K (therefore inhibitory)
Methadone binds to which opioid receptor(s)
U only
What are the side effects related to U opioid receptors?
Euphoria
Respiratory depression
Constipation
What are the side effects related to K opioid receptors?
Dysphoria
Diuresis
What are the side effects related to delta opioid receptors?
Proconvulsant
What effects to NSAIDs have?
Anti-inflammatory
Anti-pyretic
Analgesic
All effects related to decreased prostaglandin synthesis
Modulation of nociception: Prostanoid receptor (prostaglandins)
Positive effect on BK2 (Bradykinin)
Positive effect on VGNa
Modulation of nociception:
BK2 (Bradykinin)
Positive effect on VR-1
How do NSAIDs work?
Inhibit the prostanoid receptors, BK2 and VGNa
Also inhibit COX-1 or COX-2 (which leads to decrease in prostaglandin synthesis)
What are the disadvantages of NSAIDs
Multiple side effects
Severe gastric irritation
Kidney disorders
Specific COX-2 inhibitors have less side effects
COX-1 is found where?
Throughout the body (multiple uses, i.e many side effects)
COX-2 is involved in what?
Just involved in the inflammatory response specifically
