Physiology Of Pain Flashcards
Definition of pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage
What is nociception
The sensation of noxious stimuli and transmission of this sensation centrally
What are the parts of the nociceptive pathway?
Nociceptor
Dorsal root ganglion containing cell body of nociceptor
Primary synapse in dorsal horn of spinal cord
Ascending tract
Thalamus
Cortex
What is a nociceptor?
Primary afferent neurone for pain
Specialised receptors which responds to noxious stimuli
What types of nociceptors respond to what stimuli modality
Which is most common
Unimodal - mechanical distortion
Thermal - heat
Polymodal - mechanical distortion, heat, cold, chemical
Most are polymodal
Two main types of nociceptive fibres
Characteristics
Others?
C fibres - unmylinated, usually polymodal, slow conduction velocity, evoke slow response burning and aching pain,
Adelta fibres - myelinated, fast conduction velocities, fast response sharp burning, stabbing, pricking pain.
A few abeta fibres are nociceptive for mechano heat
Types of a delta fibres and difference
Type 1 mechanically sensitive, less sensitive to heat, faster conduction velocities, long latency, found on palms and soles
Type 2 mechanically insensitive, very sensitive to heat, slower conduction velocities, short latency, hairy skin only
Both sensitive to chemicals.
Functions of nociceptor other than AP in response to noxious stimuli?
Effect?
Synthesis and release of local mediators - neuropeptides (calcitonin, substance p), neurotrophins (glial cell derived neurotrophic factor), inflammatory mediators
Modulation of nociceptor gene expression, sensitisation of nociceptive pathway
What ion channels trigger nociceptive APs
Characteristics
Channels sensitive to na, k, ca or hydrogen ions
Transient receptor potential channels activated by inflammatory mediators from damaged tissue or the receptor itself (causing hyperalgesia), heat, pressure, osmotic pressure, h+, capsaicin, vibration,
Voltage gated ion channels to propagate the ap with a frequency proportional to intensity of stimulus
Inflammatory mediators and source
Effects
Prostaglandins, h+, kinins - damaged tissues, nociceptors
Arachidonites - arachadonic acid
Serotonin - platelets
Histamine - mast cells
Cytokines - immune system
Activate nociceptor (hyperaligesia)
Increase local blood flow and vascular permeability
Attraction, activation and migration of immune cells
Release of growth and tropic factors
Other than ion channels what other receptors may be present in nociceptors
Gpcrs
Cytokine receptors
Tyrosine kinase receptors
What is cell body size proportional too in the dorsal root ganglion
What does this mean for nociceptors and what proportion of the cells do these make up?
Faster neurones larger bodies
Nociceptors have relatively smaller celll bodies than aalpha and abeta fibres
Nociceptors make up about 60% of all the cell bodies there
What are the peptidergic cell bodies in the dorsal root ganglion
Those that produce peptides including cGrp, substance p and somatostatin,
Where is the dorsal root ganglion located
Relationship with other neuronal structures
In the lateral foramen between vertebral bodies with a close relationship to the sympathetic chain (linked by rami communicantes)
What is the link between the sympathetic ganglion and dorsal root ganglion in chronic regional pain syndrome
Overgrowth of fibres from the sympathetic chain over the dorsal root ganglion resulting in regional sympathetic symptoms and trophies changes in effected area.
Where do primary nociceptive fibres synapse
Laminae I, II and V of dorsal horn,
How can the primary nociceptor synapse with the dorsal horn second order neurone
Implications
Directly
Via an interneurone
With interneurones multiple sites of interaction for descending modulation, either excitatory or inhibitory
Gating of nociceptive signals (gate control theory)
At the primary synapse in the dorsal horn what neurotransmitters are involved
Excitatory - glutamate
Inhibitory - GABA, glycine
What is the effect of decending excitatory neurones on the primary synapse
Sensitisation to pain
How can the descending modulators system interact with the primary nociceptor synapse in an inhibitory pathway?
Directly at synapse, or at interneurone synapse
Via an opioid interneurone either at an interneurone synapse or inhibition presynaptically on the nociceptor axon
Types of glutamate receptors
NMDA
AMPA
Kainate
Excitory pain neurotransmitters, locations, action
Glutamate, widespread, primary afferents, acts on ampa, NMDA, kainite
Substance P, primary afferents, acts in neurokinin1 receptor
Calcitonin gene related peptide (CGRP), DRG cells, released by thermal and mechanical stimuli,
Inhibitory neurotransmitters in pain, location, action
GABA and glycine, decending modulation systems, act on ligand gated channels
Noradrenaline and serotonin, dorsal horn and descending modulation
Glutamate, dorsal horn, acts on metabotrophic receptors for inhibitory response
What types of glutamate receptors have what role in different sorts of pain
NMDA - chronic pain
AMPA - transmission of fast APs
What type of receptors are opioid and adenosine receptors?
GPCRs (metabotrophic)
Types of opiate receptor
Mu
Delta
Kappa
What is the effect of activated NMDA receptors
What blocks NMDA receptors
Calcium influx into dorsal horn neurones producing long lasting sensitisation
Ketamine
Magnesium
What type of receptor does substance p activate
NK1
Difference between gaba a and gaba b receptors
GABA a increases chloride ion conductance stabilising post synaptic membrane potential
Gaba b activate inwardly rectifiying k channel, inactivating ca channels and decreases calcium conductance causing postsynaptic membrane hyperpolarisation
Endogenous Noradrenaline neurones effect on pain
Stimulate alpha 2 recptors with inhibition of nociceptive primary afferents
What are the two types of accending pain pathway
Functions
Sensory discriminative - allows nociception quality and location to be determined
Affective pathway - triggers visceral, neurone doctrine and affective response in the brain.
In which ascending tracts do the sensory discriminative pain pathway travel
Route inc decussation
Spinothalamic
Primary afferent, synapse dorsal horn, second order decussates, ascends contralaterally to ventroposterior nucleus of thalamus
Trigeminothalmic - as above but for the trigeminal
What tract do the affective pathways of pain follow
Spinoreticular tracts
Unilateral efferent, second order branches giving an ipsolateral and contralateral branch to ascend.
Branch to many higher centres
Where are the thalamus located
Form lateral walls of third ventricle medial to internal capsule
Where in the thalamus are pain signals received
What occurs here
Ventral posterior nucleus
Mapping (localising) due to somatotophic organisation
What can cause central pain syndromes
Disruptions to the inhibitory pathways to the vpn nucleolus of the thalamus
Where in the cortex is involved in pain sensation
Responsibilities
Primary somatosensory cortex (postcentral gyrus) - localisation and duration of pain
Secondary somatosensory cortex - localisation and duration of pain
Insular cortex - emotional, affective and motivational response to pain
Anterior cingulate cortex - emotional, affective and motivational response to pain
Prefrontal cortex - anticipation, prediction and modelling on past experience. May be involved in placebo analgesia
What is sensitisation to pain
What is hyperalgesia
Sensitisation - Pain pathways have positive feedback control, enhancing nociceptors or efficacy of primary synapse in dorsal horn
Hyperalgesia - overall increase in pain response involving supraspinal mechanisms
How does peripheral sensitisation of nociceptors occur
Inflammatory response
Nociceptior becomes more responsive to stimuli so easier to trigger and gives stronger response at a given stimuli.
Can also occur in neuropathic pain conditions due to sympathetic sensory coupling
Mechanisms of central pain sensitisation
Short term homosynaptic potentiation
Long term homosynaptic potentiation
Hetrosynaptic potentiation
Transcription dependant potentiation
Loss of inhibition
Changes in synaptic architecture
Glial cell activity
What are short and long term homosynaptic potentiation?
Short - Dorsal horn cells produce progressively increasing output to prolonged c fibre stimulation (amplitude of signal increases with prolonged stimulation)
Long - a primary synapse that has already been highly activated in the preceding hours has increased efficacy due to a cascade of activation of NMDA receptors
What is heterosynaptic sensitisation?
Following minutes of nociceptive stimulation additional pathways including non-nociceptive ones (eg Abeta) triggered which also become sensitised and can persist in activation for hours
What is transcription dependant sensitisation
Intense and prolonged stimulation of nociceptors produces factors including substance p which cause increased gene transcription in dorsal horn cells in primary afferents. This causes increases in receptor proteins and others eg cox2
What is the loss of inhibition mechanism of central sensitisation to pain
Medial Compensation?
Sustained Adelta stimulation results in long term loss of inhibitory primary neurones eg. Gabaergic
Can be compensated for with gaba mimetic like gabapentin
What is the mechanism of the changes in synaptic architecture central pain sensitisation
Nerve injury results in Abeta fibres reconnecting from normal position in lamina III and IV to II causing allodynia (pain to usually non painful stimuli)
What is the glial cell activation mechanism of central pain sensitisation
Tissue injury activates glial cells facilitating primary synapse causing hyperalageaia
Mechanisms of pain modulation
Gate control
Descending modulation
Neuromodulation
What is the gate control theory of pain modulation
Interneurones activated by nociceptive primary’s are also inhibited by non nociceptive fibres supplying the same area - means activation of other sensory modality will inhibit the painful stimuli - eg rubbing the effected area or TENS
What is the decending modulators system in pain modulation
Regions involved
Two main centres
Periaquaductal grey (PAG) region in midbrain
Rostral ventromedial medulla (RVM)
PAG recieves inputs from hypothalamus, thalamus, limbic system, cortex and delivers projections to RVM. RVM also activated by opioids.
RVM activates inhibitory decending pathways and inhibits activating descending pathways to the dorsal horn.
What factors influence descending inhibition
Inputs to higher centres
Prediction
Anticipation
Affect
Emotion
Neuroendocrine axes
Autonomic function
What are the clinical effects of neuromodulators on pain?
Variable - can potentiate or inhibit
Many different types
Same modulator can have different effects if released supraspinally or spinally
Excitory pain neuromodulators and mechanism
Cholecystokinin - endogenous antiopioid
Prostaglandins - reduce inhibitory action of glycine
Dynorphine - may cause hyperalagsia at dorsal horn
Orphanin - supraspinal opioid inhibition
Inhibitory pain neuromodulators and mechanism
Opioids - PAG, basal ganglia, thalamus, descending inhibition, dorsal horn. Depends on synergistic action at two sites eg PAG and locus coeruleus
Cannabinoids - widely distributed in CNS, interact spinally and supraspinally
Orphanin - spinally produces dorsal horn inhibition
Acetylcholine - dorsal horn inhibition
What is phasic pain
Short duration intense pain from immediate tissue injury
Accompanied by reflex response (verbal or non verbal) and withdrawal/protective action
What is acute pain
Pain provoked by tissue damage
Phasic component progressing to tonic component (hours to days)
What is chronic pain
Pain persisting beyond time period of tissue healing and recovery from traumatic insult.
Associated with depression, social and behavioural dysfunction, and functional impairment
What type of receptor is an opiate receptor, how does it reduce pain?
GPCR
Activation of G protein increases ca and k conductivity causing hyperpolarisation so less APs.
What is physiological pain
Pain within normal bounds of physiological function
Warns of impending injury
What is pathological pain
Pain outside normal bounds of physiology
Follows sensitisation to pain and persist after healing has occured
Maladaptive
Causes hyperalgesia and allodynia
What is hyperalgesia
Subcategories
Enhanced pain response resulting from sensitisation
Primary - within zone of an injury
Secondary - in surrounding area to an injury due to heterotrophic sensitisation (abeta fibres from neighbouring areas becoming sensitised to stimuli)
What are punctuate hyperalgesia and allodynia
Punctuate hyperalgesia occurs with pressure (eg blunt pin) by small diameter nociceptive fibres
Allodynia is a hyperalagesic response to light stroking touch due to low threshold mechanoreceptors - occurring due to synapse remodelling with abeta fibres activating ascending pain reflex.
Types of endogenous opioids. What are they? What receptors do they trigger?
Short polypeptides
Leuenkephalin - d > k»_space; m
Metenkephalin d > m»_space; k
Beta endorphin d/m»_space; k
Dynorphin k
Endomorphin m
Nociceptin ORL1
Characteristics of complex regional pain syndrome
Types
Chronic pain accompanied by abnormal perfusion, oedema and sweating in effected area. Tropic changes to skin hair and nails + muscle waisting.
Type I - no nerve injury
Type 2 - nerve injury
Prevalence of severe phantom limb pain in amputee
5-10%
Causes of painful neuropathies
Diabetes
Hypothyroid
Alcohol
Beriberi
Cytotoxic drugs
Isoniazid
What is neuropathic pain
Pain from primary lesion or dysfunction of the nervous system
Why is visceral pain Pooly localised
Sparse innervation and spread of spinal input over several segments with convergence of input with somatic afferents or other viceral afferents leading to referred pain,
What sort of pain has the strongest autonomic and emotional associations
Viceral
What is the significance of the emotional cognitive and behavioural responses to pain
Emotional - pain produces anxiety anger, fear and depression. Depression and anxiety are thought to increase intensity of pain thus their management is vital in pain management
Cognitive - pain is processed and linked to past experiences and beliefs. Maladaptive cognitive responses such as catastrophising and lack of self efficacy are detramental. Can be used to develop coping stratergies for the pain
Behavioural - learned behaviour from the emotional and cognitive response. Can be adaptive or maladaptive. Can be manipulated as part of management.
What is the mainstay of acute pain management? Other factors?
Managing nociceptive process with drugs
To some extent na ageing anxiety and fear
What are key mechanisms in chronic pain that impact on different management compared to acute?
Sensitisation and supraspinal mechanisms
Mechanisms of chronic pain management
Pharmacological
Local anaesthetic techniques
Physiotherapy
Complementary techniques
Examples of local anaesthetic techniques used in chronic pain management
Nerve blocks,
Sympathetic blockade
Neurolytic blockade with phenol or radio frequency lesioning
Elements of physiotherapy in chronic pain management
Massage
Manipulation
Injections
Acupuncture
Heat and ice application
Ultrasound
Complementary pain management techniques and brief desription
Osteopathy - msk manipulation allowing body to heal itself
Chiropractic - msk manipulation as above with focus on spine
Acupuncture - dry needling points to improve flow of energy - ? Endorphin release
Reflexology - stimulation of nerves to treat pain
Homeopathy - imprinting of solute on solvent by dilution?
Effect of TCAs on pain management
Inhibit presynaptic uptake of serotonin and NA in decending inhibitory system
Blocks na and ca ion channels
Blocks muscarinic and histamine receptors
Role of anticonvulsants on pain
Block voltage dependent na channels
Carbamazepine is serotonergic
Effect of gaba mimetic (gabapentin and pregabalin) on pain
Increases gaba concentration for inhibition
Effect of antispasmodics on pain
Buscopan relaxes smooth muscle
Backoofen relaxes skeletal muscle
Effect of alpha 2 agonists on pain
Systemic effect on reducing neuropathic pain
Local effect reducing allodynia
Effect of tramadol on pain
Opioid action
Increases serotonin and na in deceasing inhibition
