Pharmacology CNS Pain Flashcards
How is pain a protective response?
Communicates peripheral damage to brain and raises awareness of damage
Helps immobilise damaged areas to facilitate healing
Define pain:
An unpleasant sensation perceived as arising from a specific region of the body and commonly produced by processes that damage or are capable of damaging bodily tissue
Name the different types of pain:
Somatic pain
Visceral pain
Neuropathic pain
Sympathetically maintained pain
Describe somatic pain:
From cutaneous/ musculoskeletal tissue or peritoneal membranes
e.g post-operative, post exercise, mild trauma
Describe visceral pain:
The thoracic or abdominal organs
e.g post-operative, cancer related, traumatic injury
Describe neuropathic pain:
From injury to the peripheral or CNS- specific damage to sensory neurons (nociceptive neurones)
e.g amputation (surgical or traumatic), T2D
Describe sympathetically maintained pain:
Sensitisation of CNS causes neuropathic- like pain in distribution of sympathetic nerve (chronic)
e.g complex regional pain syndromes (CRPS)
What is nociception?
Underlying process sensing local tissue damage ≠ pain
Detection of noxious stimuli (with intensity and quality sufficient to trigger reflex withdrawal, autonomic responses and pain)
What are nociceptors?
Sensory receptors
Specialised endings of 1º afferent neurones found throughout peripheral tissues
They innervate skin, muscles, joints found all over body and are responsible for trasnduction of noxious stimuli
Name types of noxious stimuli?
Mechanical: pinching, cutting, scratching
Thermal: temp extremes
Chemical
What are polymodal nociceptors?
Nociceptors activated by a variety of damaging stimuli
Describe the structure of nociceptors and their regulation:
NOT protein receptors, they are naked nerve endings
Do not up or down regulate in response to stimulation but perception of pain is modifiable (modifying nociception)
Name the different types of sensory nerve fibres?
A*
B
C*
*Important for nociception
What is the diameter (µm) for the different sensory nerve fibres?
A: 2-20
B: <3
C: <1.5
What is the conduction (m/s) for the different sensory nerve fibres?
A: 5-100
B: 3-15
C: 0.1-2.5
Which of the sensory nerve fibres are myelinated?
A and B
Not C
What is the function of B sensory nerve fibres?
Pre-ganglionic
Autonomic
Vascular SM
What is the function of C sensory nerve fibres?
Pain
Temp
Post-ganglionic
Autonomic
Name the different subtypes of the A sensory nerve fibres?
Aa
AB
Agamma
Ad
What is the function of the Aa sensory nerve fibre?
Efferent, motor, somatic, reflex activity
What is the function of the AB sensory nerve fibre?
Afferent, innervate muscle, touch, sensation, pressure sensation
What is the function of the Agamma sensory nerve fibre?
Efferent, muscle, spindle tone
What is the function of the Ad sensory nerve fibre?
Afferent, pain, cold, temp, tissue damage indication
Associated with nociception
Name and describe the two types of neurones carrying noxious stimuli?
Ad fibres- normally in skin, sharp pricking pain
C fibres- dull, longer lasting, aching
What is the first and second pain?
First- informative, forces movement away from danger
Second: punishing pain, changes behaviour
Name the 4 processes of nociception:
Detection
Transmission
Perception
Modulation
Define detection in nociception:
Noxious stimuli-> release of chemical mediators from damaged cells
Chemical mediators activate/ sensitise nociceptors
Cell membrane becomes depolarised and AP generated
Define transmission in nociception:
Transduction site to afferent pain fibres (Ad and C) to dorsal horn of spinal cord to brain stem to thalamus, cortex and higher brain
Define perception in nociception:
Affective- motivational, sensory- discriminative, emotional and behavioural experience
Activation of multiple areas: reticula system, somatosensory cortex, limbic system
Define modulation in nociception:
Changing transmission of pain impulses in spinal cord via complex Descending Modulatory Pain Pathways (DMPP)
Excitatory- increased pain transmission
Inhibitory- decreased pain transmission
How are nociceptors activated?
Trauma (surrounding tissue/ cell damage) leads to release of chemical mediators (intracellular contents) from damaged cells
Chemical mediators activate/ sensitise nociceptors (detected by nociceptive fibres by the ion channels on fibres)
When 1º afferent fibres become sensitised, cell membrane becomes depolarised and AP demonstrated
Name chemical mediators which can activate nociceptors:
ATP
Immune cells: mast cells (histamine, bradykinin), neutrophils, PGs
Glutamate
5-HT
H+ (acidify local area, stim other signals)
Substance P CGRP
NGF- nerve GF
Neuropeptide gamma
Name the different ion channels which are found on the nociceptor afferent terminal:
ASIC (cationic)- activated by high H+ conc
P2Xr, P2X3 on afferent (cationic)- activated by high ATP conc
VG Na+ channel- AP generation
TRPV1
Describe what the TRPV1 ion channel on nociceptors is activated by:
Non-selective cation channel- activated by many different stimuli e.g:
H+ (acidic pH, less than 5.5)
Noxious heat (more than 43ºC)
Chemicals (capascain)
Endovallinoid chemicals (endogenous)
Describe the consequence of activation of the TRPV1 ion channel:
Will cause cation influx (Na+, Ca2+), which will drive depolarisation and activation leading to excitation
Name GPCR which can enhance nociception:
B2 receptor
Prostanoid receptor (aka EP receptors)
How can the B2 receptor enhance nociception?
Responses to bradykinin (produced during tissue injury- an inflammatory mediator) which leads to activation of PKC which causes phosphorylation of TRPV1 which sensitises and enhances depolarisation as increase opening of channels
Causes release of PG
How can the prostanoid receptor enhance nociception?
Prostanoid receptor responds to PGs which can stimulate activity of PKA which can phosphorylate and enhance VG Na+ channels
They can also inhibit K+ channels (PGE2) which increase depolarisation of nociceptive afferent terminal
How can NGF enhance nociception?
Can be release from afferent terminal themselves and can act on TrKA to have long lasting effect on nociceptive activity by affecting gene expression of ion channels such as TRPV1 and can also increase activity of various ion channels by phosphorylation
Name and describe subtypes of the TRP ion channel which are sensitive to noxious cold rather than heat:
TRPA1 and TRPM8
Cold sensitive ion channels, also activated by chemicals
Describe peripheral modulation in terms of C fibres:
Chemical mediators act synergistically
Reduce threshold of C fibres, increase activity for a given level of stimulus
C fibre activity causes peripheral release of neuropeptides which cause release of inflammatory mediators and NGF which leads to the +ve feedback so increase sensitivity of the neurone
Name neuropeptides peripherally released by C peptide:
Substance P
CGRP (calcitonin gene related peptide)
What does hyperalgesia mean?
Increased sensitivity to pain
Name the 2 pathways in transmission:
Ascending and descending pathways
Describe the ascending pathway:
Trauma- AP propagated along nerve fibre to spinal cord to dorsal horn of spinal cord where they synapse with other neurone (in spinothalamic tract) to the brain
Describe the descending pathway:
From brain to spinal cord to modulate the amount of info being passed through the ascending pathway
Name the 5 NaV subtypes:
NaV:
1.1
1.6
1.7
1.8
1.9
Name the main neurotransmitter in nociception:
Glutamate- excitatory
Describe mutations in the NaV channel relating to human pain:
Mutations in NaV 1.7 (essential in nociception) cause erythromelalgia and paroxysmal extreme pain disorder where as a loss of activity of NaV 1.7 means people do not feel pain
Similar picture emerging for 1.8 and 1.9
Describe the structure of the NaV:
24 TMD clustering around central aq pore
DI to DIV (6 per part)
Name the layers of the dorsal horn:
Layer I- superficial
to
Layer VI- deepest
Describe the function of the dorsal horn in nociception:
Axons coming into dorsal portion of spinal cord where they synapse to next neurone
Name and describe which layers the Ad fibre synapses in:
Fast pain
Synapse in Lamina I, synapse in neurone which sends axon to thalamus
Ad fibres can also enter lamina V and synapses with neurones there they send their axons to the brain stem and thalamus
Mechanosenstive AB fibres come in and synapse with different neurones in layers III,IV,V
Name and describe which layers the C fibre synapses in:
Enter into lamina I and II where they make connections to other neurones
Describe the structure of lamina II of the dorsal horn:
Densely packed layer of the dorsal horn, contains lots of short interneurons (can be both inhibitory/ excitatory) and act as input and output modulators, to regulate what for through the spinal cord
Describe the structure of lamina V of the dorsal horn:
Receive several inputs from different fibres
Receive direct input from Ad fibres, receive input from C fibres as C fibres interacting with dendrites of lamina V neurons
Lamina V also receive input from visceral nociceptors as well as cutaneous
Describe where inhibitory interneurones are found in the dorsal horn:
Present throughout the dorsal horn
Common in substantia gelatinosa (lamina I-II)
What is referred pain?
Inputs from visceral (organs) nociceptors from laminae V may result in somatic (skin) perception of pain
Where location info associated with noxious insult is misread/ misinterpreted by brain
What is referred pain due to?
Possibly due to convergence of multiple nociceptor afferents on a single spinothalamic tract via dorsal horn e.g heart attack patients will complain about pain in left arm, visceral pain is rare compared to somatic pain
Brain localises visceral pain to somatic structure whose 1º afferents converge at same point on spinothalamic tract
Which lamella do AB fibres bind to?
Mechanoreceptor, III, IV, V, VI
Which lamella do Ad fibres bind to?
Mechanoreceptor, II, III
Nociceptor, I, V
Which lamella do C fibres bind to?
Nociceptor, thermoreceptor, mechanoreceptor, I, II
What is gate control in nociception?
Inhibitory modulation- using inhibitory interneurons
What is the role of inhibitory interneurons?
Important role in regulating the amount of transmission of the nociceptors and how much of that signal is sent to the brain
They can control pain transmission, so underlies the idea of gate control theory
What if inhibitory internerons are dysfunctional?
Loss of inhibition can result in hyperalgesia
Disinhibition can enable AB primary afferents to engage, normally innocuous stimuli (doesnt hurt) are now perceived as painful
Where does the descending inhibitory pathway originate in the brain?
2 distinct areas:
-periaqueductal gray- uses 5HT as primary NT
-locus ceruleus- uses NA as primary NT
Enkephalins (endogenous opioids) are important in stim of these pathways
What is the descending inhibitory pathway?
Directly inhibit transmission through central synapse or can stimulate local inhibitory interneurons in substantia gelatinosa
Describe inhibitory central modulation:
Short inhibitory interneurons in the dorsal horn of the spinal cord modulate transmission at the first synapse
They mediate an inhibition of transmission (gate keeps)
Enkephalins important in this process
Describe excitatory central modulation:
Dorsal horn cells that are normally only activated by nociceptors start to respond to low threshold afferents (AB)
Innocuous peripheral stimuli evokes painful sensation (increase nociceptive transmission):
-hyperalgesia
-allodynia (pain caused by non noxious stim)
-spontaneous pain (pain without precipitating stim)
Describe neuropathic pain in central modulation:
Thought to be due to long lasting enhancement of synaptic transmission through spinal cord
Glial cells can contribute to increased firing which can exacerbate this
Which 3 places can central sensitisation occur?
-Enhancement of signalling-NMDA mediated signalling
-Switching off of inhibitory interneurons- disinhibition
-Impact of local glial cells- microglia activation
Describe central sensitisation through NMDA:
Alteration in glutamatergic neurotransmission/ NMDAr mediated hypersensitivity:
-spinal cord central sensitisation is dependent on NMDA- mediated elevations of cystolic Ca2+ in the post synaptic neuron
-similar idea behind long term potentiation
Describe central sensitisation through disinhibition:
Loss of tonic inhibitory controls (disinhibition)
-GABAergic of glycinergic inhibitory interneurons lose control
-enhances depolarisation and excitation of projection neurones
Describe central sensitisation through glial cells:
Glial neuronal interactions
-activated microglia release variety of different signalling molecules including cytokines (ATP etc) which enhance signalling across central synapse (enhance neuronal central sensitisation) and nerve induced persistent pain
What is the effect of the cytokine release in glial central sensitisation?
ATP acting on P2X4 r releases brain derived neurotrophic factor (BDNF) from microglia which alters the effect of GABA on projection neurons- changes to excitatory so GABA enhances signal instead
Name the 4 opioid receptors:
DOR- delta opioid receptor
MOR- mu opioid receptor
KOR- kappa opioid receptor
ORL1- orphan receptor
Describe the structure and signalling of the opioid receptors:
All GPCRs
All signal through Gai/o
May splice variants have been identified for MOR
Describe the first step in the opioid receptor signalling:
Opioid agonist- G protein activation
Activation of Gai (intracellular side) regulates activity of AC and decreases cAMP
GBy can regulate activity of VG Ca2+ channels- causing them to become inhibited so decreases neuronal excitability and in some cases (especially in pre-synaptic) can prevent NT release
GI can also increase K+ (Kir3 (Girl) channels) conductance across plasma membrane which leafs to hyperpolarisation which decreases neuronal excitation
Describe the remaining steps in the opioid receptor signalling:
- Receptor phosphorylation
3a. Arrestin recruitment
3b. Internalisation of GPCR into cells so takes them of cell surface - MAPK signalling to ERK, P38, JNK
- Recycling
Describe the important of the MOR receptor:
Important in acute pain signalling
Clustered around superficial layer of dorsal horn- lamina I
Name the endogenous/ synthetic agonists at the MOR receptor:
Morphine induced effects require MOR
Morphine is a partial agonist
B-endorphin, met-encephalin have activity
DAMGO is a synthetic peptide agonist
CTOP is a synthetic peptide antagonist
What is the effect of stimulating the DOR and KOR receptor?
Can give analgesia but with other SEs
Describe the likelihood of analgesia at each opioid receptor:
MOR: +++
DOR: +(spinal)
KOR: +(peripheral)
ORL1: +(spinal)
Describe the likelihood of respiratory depression at each opioid receptor:
MOR: +++
DOR: ++
KOR: -
ORL1: -
Describe the likelihood of sedation at each opioid receptor:
MOR: ++
DOR: -
KOR: ++
ORL1: -
Describe the likelihood of dependence at each opioid receptor:
MOR: +++
DOR: -
KOR: -
ORL1: -
Describe the likelihood of euphoria at each opioid receptor:
MOR: +++
DOR: -
KOR: -
ORL1: -
Describe the likelihood of hallucinations at each opioid receptor:
MOR: -
DOR: -
KOR: +++
ORL1: -
Name and describe the sites of action of opioids:
Spinal cord
Periphery
Central (brain)- multiple layers including descending pathway
Describe the effect on the spinal cord an opioid has:
Act to decrease transmission of nociceptive signals through dorsal horn by suppressing transmission through central synapse: presynaptic and post synaptic
Describe the effect on the periphery an opioid has:
Inhibit/ reduce nociceptive afferent firing (C and Ad fibres)
Where do the opioids work in the brain?
Works on NRPG in brain so stim NRM which inhibits 5HT and Enkephalin opioids preventing detection of noxious stimuli in periphery
Opioids can have excitatory effects in descending inhibition pathway, as mu-opioid receptor present on GABA containing inhibitory neurons that regulate this pathway
By inhibiting activity of these GABAergic neurons, allows inhibitory descending neurons to fire so can fire in dorsal horn
Name endogenous opioids:
Several families of opioid peptides, enkephalins, dynoprhin and endorphins
What are the causes of neuropathic pain?
CNS disorders: stroke, multiple sclerosis
Peripheral nerve damage:
-diabetic neuropathy, HZV, traumatic/surgical amputation
How does gabapentin/pregabalin work for pain relief?
Thought bind to VG Ca2+ channel a2d subunit and decrease NT release
How do TCA and SNRIs work for pain relief?
Potentiate descending inhibition by modulating 5HT and NA levels, preventing reuptake
How does capsaicin patches work for pain relief?
Peripheral
TRPV1 agonist
How does lidocaine work for pain relief?
Local anaesthetic
How does ziconotide work for pain relief?
Inhibits Ca channels- CaV2.2
Similar effect to gaba/pregab
How does ketamine work for pain relief?
NMDAr blocker- suppress neurotransmission through central synapse
