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