Pain pharmacology Flashcards
What are the 4 types of pain?
- Somatic:
Cutaneous, musculoskeletal tissue, peritoneal membranes
e.g post-op, post-exercise, mild trauma - Visceral:
Thoracic or abdominal organs
e.g. post-op, cancer-related, traumatic injury - neuropathic:
From injury to peripheral or central nervous system
e.g. amputation, T2DM nerve pain - Sympathetically-maintained pain:
Sensation of CNS causes neuropathic-like pain in distribution of a sympathetic nerve
e.g. complex regional pain syndrome (CRPS)
What is nociception?
The detection of noxious stimulus (painful stimuli) by sensory receptors (nociceptors)
What are nociceptors?
Nociceptors are specialized nerve endings that respond directly to noxious stimuli and indirectly to chemicals.
- They are on endings of primary afferent neurones in the PNS and cause transduction of noxious stimuli (stimuli can be mechanical, thermal, chemical, polymodal).
- They are NOT protein receptors, rather naked nerve endings- therefore there isn’t up or down regulation in response to stimulation but perception of pain/nociceptions is modifiable.
What are the 3 types of nerve fibres?
A, B & C
Describe the A nerve fibres.
A nerve fibres:
- 2-20 µm
- are myelinated
- 5-100 m/s conduction velocity
- 4 sub-types:
A𝛂
Aβ- touch, pressure
A𝜸
A𝞭- nocieption
Describe the B nerve fibres.
- <3µm
- Myelinated
- 3-15 m/s conduction velocity
Describe the C nerve fibres.
- <1.5µm
- 0.1 to 2.5 m/s
- Not myelinated
- involved in nociception
What types of neurones are involved in carrying noxious stimuli and what are their roles?
- Aβ (delta) fibres are commonly found in the skin are involved in 1st pain: informative and forces the movement away from danger- causes quick, sharp, shooting pain
- C fibres: Are involved in 2nd pain- this is punishing pain the changes our behaviour to not repeat the dangerous action again. is a dull, longer-lasting, burning pain.
LOOK AT DIAGRAM
What are the 4 process of nociception?
(Is broken down in subsequent flashcards)
DETECTION: Noxious stimulus → release of chemical mediators from damaged cells.
Chemical mediators activate/sensitise nociceptors.
Cell membrane becomes depolarised and AP generated.
TRANSMISSION: Transduction site → afferent pain fibres (Aδ and C) → dorsal horn of spinal cord → brainstem → thalamus, cortex and higher brain
PERCEPTION: Affective-motivational, sensory-discriminative, emotional and behavioural experience.
Activation of multiple brain areas: Reticular system, somatosensory cortex, limbic system.
MODULATION: Changing transmission of pain impulses in spinal cord via complex Descending Modulatory Pain Pathways (DMPP)
Excitatory - ↑ pain transmission
Inhibitory -↓ pain transmission
Discuss the Detection part of nociception?
First is activation of nociceptors:
- When cells or tissues become damaged, they release their intracellular contents- chemical mediators e.g.
ATP
Glutamate
Immune cells- mast cells neutrophils e.g. which release
Bradykinin
Histamine
Cytokines
H+ ions- changes in pH causing acidification of local area
5-HT
- These Chemical mediators activate/sensitise the nociceptors. Nociceptors then release neuropeptides e.g. CGRP, Substance P, MGF, Neuropeptide-y - these act on surrounding tissues to cause activation of immune cells and blood vessels.
- The chemical mediators are detected by nociceptor fibres by ion channels on receptors= primary afferent fibres become sensitised, leading to strong depolarisation of the membrane and action potential firing. This leads to transmission of the signal to the CNS- brain and spinal cord. HOW:
ION channels:
- The ASIC channel, repsonds to the high proton concentration and P2X receptors respond to high ATP concentration = activation of these cation-selective channels leads to depolarisation of nociceptive fibre = activation of voltage-gated sodium channel and generation of action potential.
- TRPV1- This channel is activated by protons, acidic pH, noxious heat (threshold around 43 degrees), chemicals e.g. capsaicin and endovanilloids. These all activate TRPV1 which leads to a sodium and calcium ion influx = depolarisation = activation of voltage gated sodium channels = action potential firing
GPCRS:
- B2 receptors (GPCR) respond to bradykinin (Produced during tissue injury by cleavage precursors): are couples to protein kinase C (activated) - phosphorylation of TRPV1 and activation of the TRPV1 ion channel and depolarisation. Bradykinin can also cause release of prostaglandins (production occurs in inflammation and tissue ischemia- PGE2 causes K+ channel inactivation and phosphorylationof TrPV1 via EP receptors) which act on the prostanoid receptor (EP) to stimulate Protein kinase A= phosphorylates and enhances ion channels e.g. voltage gated sodium channels and inhibit potassium channels = drive depolarisation. NOTE, NSAIDs inhibit prostaglandin synthesis and so causes analgesia.
- Nerve growth factor (NGF) is released from afferent neurones and binds to the TrKA receptor- Three major signaling cascades initiated by TrkA activation include the phospholipase C-γ (PLCγ) pathway, the mitogen-activated protein kinase (MAPK)/Erk pathway, and the phosphoinositide 3-kinase (PI3K) pathway = phosphorylation
Peripheral modulation:
Chemical mediators act synergistically= Reduce threshold of C fibres, increasing activity for a given level of stimulus
C-fibre activity causes peripheral release of neuropeptides
Substance P,
CGRP (calcitonin gene-related peptide)
These cause release of inflammatory mediators and NGF (nerve growth factor) - +ve feedback – increases sensitivity of the neurons
Sustained release can therefore cause increased sensitivity to pain (hyperalgesia)
What is TRPV1?
Transient Receptor Potential cation channel subfamily V member 1
Major role in body temperature regulation – important peripheral detector.
If stimulated, leads to a sensation of burning - important in nociception.
Activated by:
* pH<5.5
* Heat > 43°C
* Allyl isothiocyanate (mustard and wasabe)
* Capsaicin (vallinoid in chilli peppers)
What is NGF?
NGF = nerve growth factor
- Acts on TrkA receptors
- Causes upregulation of NaV channels
- Signals to increase activity of TRPV1 via tyrosine kinase activity (phosphorylation)
- People with mutations in TrkA have a congenital insensitivity to pain
A mutation in which receptor may lead to a congenital insensitivity to pain?
TrKA
Discuss the transmission part of nociception?
Transduction site → afferent pain fibres (Aδ and C) → dorsal horn of spinal cord → brainstem → thalamus, cortex and higher brain
Aδ and C fibres synapse with secondary afferent neurones in the dorsal horn of the spinal cord.
Complex interactions occur in the dorsal horn between afferent neurones, interneurones and descending modulatory pathways (see below). These interactions determine activity of the secondary afferent neurones. Glycine and gamma-aminobutyric acid (GABA) are important neurotransmitters acting at inhibitory interneurones
Ascending pathway is the nociceptive fibres – Ad or C-fibres.
Starts in the periphery where nociceptor endings are located, travels to the spinal cord where they terminate in dorsal horn of the spinal cord in different laminae (layers)
Synapses with a second neuron which projects to the brain, ascends through spinothalamic tracts to somatosensory cortex, limbic system, cingulate and insular cortex areas.
The ascending pathway is Excitatory - synapse uses glutamate as NT
Not a single pain centre in the brain
Descending pathways – originate in the brain – distinct regions involved– PAG and LC and project down to the spinal cord where they can modulate the activity of the central synapse in the spinal cord.
PAG = serotonergic neuron; LC is a noradrenergic neuron
Can activate the short inhibitory interneurons in the spinal cord which will inhibit transmission
Descending inhibitory neurons could directly inhibit transmission through the central synapse by releasing endorphins/enkephalins to act on opioid receptors – inhibitory GPCR which can inhibit neurotransmission by acting on NT release (inhib CaV channels) or on action potential generation (by activating K channels and increasing hyperpolarisation).
Major differences – different NT, effect – excitatory vs inhibitory, directionality of signal, origination/terminating
NaV channels are critical for propagation of the action potential
Sub-types:
Nav 1.1, 1.6, 1.7,1.8, 1.9
Which NaV channel is essential for nociception and what happens if there is a mutation in this channel?
NaV 1.7:
- Mutations in this channel can cause pain disorders e.g. erythromelalgia and paroxysmal extreme pain disorder.
- However, loss of activity at NaV 1.7 can cause insensitivity to pain- don’t feel pain.
- A similar idea is emerging for NaV 1.8 and 1.9 too.
