Inflammation and Neuropathic Pain Flashcards
Define pain as defined by the international association for the study of pain.
an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.
What is nociceptive pain?
− Nociceptive pain results from the detection of intense or ‘noxious’ stimuli by specialized high-threshold sensory neurons (nociceptors), transduction of this stimulus to an electrical impulse, conduction of action potentials to the spinal cord and onward transmission of the warning signal to the brain where it is perceived.
− It is imperative that the body is aware of potentially damaging stimuli to guard against tissue injury
− So, noxious stimuli are stimuli that threaten to damage tissues of the body.
− Loss of nociception, as in hereditary disorders associated with congenital insensitivity to pain, leads to repeated injury.
Describe the organisation of the sensory nervous system
• A sensory axon (part of the peripheral nervous system) has peripheral terminals with the receptors
• The cell body of the sensory axon resides in the dorsal root ganglia
− One axon from the peripheral terminal to the cell body
− One axon projectes from the cell body up to the spinal cord
• In the brain, it will synapse with motor neurons to respond to the stimulus.
Describe the 3 forms of sensory neurons
Aa/Ab
Large, 40-80um
Myelinated
Fast, 40-120m/s dude to saltatory conduction
Proprioception → sensing of movement, joints and joint position. Enables us to know where we are in space without having to look
Low threshold mechanoreception – response to mechanical pressure or touch.
Ad Small-medium 15-50um Thinly myelinated Medium, 10-30m/s High threshold mechanoreception (higher stimulus)
C Small 10-25um No myelination Slow, 0.5-2m/s Thermoreception High threshold mechano/thermo/chemoreception Silent polymodal nociceptors
Describe the nociceptors
- Cold → TRPM8
- Heat → TRPV1 & TRPV3
- H+ → TRPV1 & ASIC]
- Mechanical → P2X/P2Y & TRPA1
- Capsaiin in chillies is a TRPV1 agonist – we feel heat when we eat chillies because they activate the heat receptor
- When we have menthol we feel cold because it activates the cold receptor
How do nociceptors respond to pain (direct and indirect)
- Peripheral terminals are not alone – there exists around them a variety of other cell types
- In physiological pain, nociceptors respond to acute tissue damaging stimuli either directly through transduction of the stimulus energy by nociceptors, or indirectly through activation of TRP channels on cells such as keratinocytes and/or the release of intermediate molecules such as ATP which in turn act on sensory neuron receptors.
- Sensory afferents are mostly glutaminergic (releasing glutamate) and peptidergic (releasing substance P)
Describe the laminar organisation of the spinal cord and primary afferent inputs
- Primary afferents terminate at discrete areas of the spinal cord
- Nociceptors (Ad and C-fibres) terminate right at the top of the dorsal horn (the superficial dorsal horn)
- The faster, myelinated Ab afferents terminate lower down
- Most neurons in the spinal dorsal horn receive inputs from several sensory afferents (wide dynamic range) – respond to brush, touch, tap, pinch, pressure etc…
- Others are nociceptor specific neurons – only respond to noxious stimuli like the pinpricks and pinch
What are the 3 types of pain
Acute nociceptive
Inflammatory
Neuropathic
Describe acute nociceptive pain
- High threshold, stimulus dependent pain (thermal, mechanical or chemical stimuli)
- Mediated by high-threshold, unmyelinated C-fibres or thinly myelinated Ad fibres feeding into nociceptive pathways of the CNS
- Pain evoked in a graded response by appropriate high intensity (noxious) stimuli
- For nociceptive pain to subserve its protective function, the sensation must be so unpleasant that it cannot be ignored.
- Nociceptive pain occurs in response to noxious stimuli and continues only in the maintained presence of noxious stimuli
- Adaptive, and serves a protective purpose → good pain!
Describe inflammatory pain
• Active inflammation – occurs in response to tissue injury and the subsequent inflammatory response.
− TNFa, IL-1B, IL-6 ,NO, Bradykinin etc… released by inflammatory cells activated in response to tissue damage can all activate nociceptors.
• Sensitisation → Heightened sensitivity occurs within the inflamed area and in contiguous noninflamed areas as a result of plasticity in peripheral nociceptors and central nociceptive pathways. Because the pain system after inflammation is sensitized, it no longer acts just as a detector for noxious stimuli but can be activated also by low-threshold innocuous inputs.
− Here we have the involvement of second messenger systems – Isnt a straightfoward transit of information – second messengers can amplify the response à this is known as peripheral sensitisation.
• Adaptive
• Pain evoked by low and high intensity stimuli BUT
• This is protective during healing responses – To aid healing and repair of the injured body part, the sensory nervous system undergoes a profound change in its responsiveness; normally innocuous stimuli now produce pain and responses to noxious stimuli are both exaggerated and prolonged. For example, if you had broken your risk, you may experience pain when your wrist is just lay on a surface – this wouldn’t normall trigger pain, but after tissue injury, innocuous stimuli are painful. It is alerting you that there has been a problem, and not to damage the body more.
• Reversible → typically disappears after resolution of the initial tissue injury. However, in chronic disroders such as RA, the pain persists for as long as inflammation is active.
Define neuropathic pain
- Pain initiated or caused by a primary lesion in the nervous system
- Ongoing, non-stimulus dependent pain
Name the 6 causes of neuropathic pain with examples.
- Traumatic → e.g. nerve entrapment, axotomy
− eg, from carpal tunnel syndrome or amputation. - Central → e.g. stroke, spinal cord injury, multiple sclerosis
- Neurotoxic → eg. microtubule-stabilizing agent (MTSA) induced neuropathy
− Chemotherapy agents can cause microtubules and peripheral nerves to die back, causing neuropathic pain. - Infectious → e.g. HIV-neuropathy and post-herpatic neuralgia
− Shingles (post herpatic neuralgia) can persist for up to a year - Metabolic → e.g. diabetic neuropathy and alcohol-induced neuropathy
- Idiopathic (unknown cause).
Give an example of neuropathic pain.
50% of diabetic patients and ~ 30% of HIV-positive patients will present with some degree of DPN (from mild-chronic)
• Distal axon degeneration and reduced ability of nerves to regenerate.
• Numbness and loss of protective reflexes
• Neuropathic pain with a glove-stocking distribution (arms and legs)
• In diabetic paients, there is a decrease in the number of nerve fibres as you move from thigh to calf. This not only causes numbness, it can cause neuropathic pain. It is hard to treat – most analgesics will not work.
What are the features of neuropathic pain?
- Marked neuroimmune component
- Sensititisation → Once neuropathic pain is generated, the sensory hypersensitivity typically persists for prolonged periods, even though the original etiological cause may have long since disappeared, as after nerve trauma. The syndrome can nevertheless progress if the primary disease, such as diabetes mellitus or nerve compression, continues to damage the nervous system.
- Spontaneous and evoked by low and high intensity stimuli → even in the absence of stimuli, patient will report ongoing pain.
- Maladaptive nad persistent
- Abnormal amplification
- Serves no useful purpose
- Not well managed → bad pain!
Describe the prevalance for neuropathic pain and potential risk factors
- It is not an inevitable consequence of neural lesions → the pain associated with acute neural damage usually transitions to chronic neuropathic pain in the minority of patients
- For damage of a small neve, risk of persistant pain is 5%, whereas a large nerve such as the sciatic nerve is 30-60%
- Understanding why one individual may develop chronic pain and another doesn’t is crucial to developing strategies to abort such transitions
- Injury such as brachial avulsion during birth does not produce pain in neonates, but produces chronic neuropathic pain in 40% of adults → may depend on the maturity of the nervous system
- Assocaited risk factors for the development include gender, age, anatomic site of injury and severity of pain at the time of event
- Emotional and cognitive factors influence how patients react to chronic pain, but less certain if these contribute to its development.
What are the two types of neuropathic pain
• Stimulus-evoked pain:
− Hyperalgesia → enhanced pain evoked by a noxious stimulus –thermal or mechanical
− Allodynia → pain evoked by a normally innocuous stimulus
• Spontaneous pain:
− Often described as burning, tightness accompanied with shooting or stabbing pains.
Why are co-morbidities common with neuropathic pain?
− Imagine an excruciating pain every time clothes touch your skin, spontaneous burning that feels like boiling water, bursts of “pins and needles” in your feet when you walk, a continuous crushing pain after an amputation as if your phantom foot is being squeezed, a band of searing pain around your body at the level at which you have lost all sensation after a spinal cord injury.
What are the pre-clinical models of neuropathic pain, and how can we assess for them pre-clinically.
Experimental models of neuropathic pain typically involve unilateral injury to rodent peripheral nerve.
- Chronic constriction injury
- Full or partial sciatic nerve ligation/crush
- Spinal nerve ligation
- Nerve transection (axotomy)
But, there are also animal models of specific neurotoxic, infectious and metabolic neuropathies.
− eg) Streptozocin induced diabetics for diabetic neuropathy, paclitaxol (chemotherapy neuropathies).
Most people with neuropathic pain have specific neuropathies, like diabetes. So models should focus more on this rather than simple models of neuropathic pain.
Assessing pre-clinical models of neuropathic pain:
We can test thresholds using eg):
− Von Frey Filaments (mechanical sensitivity) → if hypersensitive, very fine filaments will be enough to evoke a response.
− measure the existence of pain through behaviors such as withdrawal, licking, immobility, and vocalization.
− the filaments are pieces of nylon rod of varying diameters
− Is a test of mechanical nociception
− The animal stands on an elevated mesh platform, and the filaments are inserted through the mesh to poke the animal’s hindpaw
− Hargreaves IR/hot plate (thermal sensitivity)
− A heat-conductive surface, such as porcelain or metal, is heated to a temperature that will induce a nociceptive response in an animal subject – normally 50–56 °C.[2] The subject is then placed onto the surface and prevented from leaving the platform by blockades. The latency to pain-reflex behavior is measured
These measure stimulus-evoked thresholds.
• Paw withdrawal threshold or latency – test for presence of hypo/hypersensitivity
• Left versus Right thresholds for nerve injury, or vs sham or naïve animal depending on model
- Non-stimulus evoked measures are not easy to quantify in animals, and this is really what we want to understand – the chronic ongoing pain.
- However, you can look at behavioural changes, e.g. thigmotaxis/open field, burrowing, changes in gait, expression), place preference test
How do we assess pain clinically?
• Easier to quantify pain in patients than rodents
• Most common method is McGill quesionairre approach
− Rates in terms of feeling, eg) throbbing, shooting, stabbing, sharp, cramping
− Rates each of these as mild, moderate, severe
• Can also use the Wong Baker face scale (hurts a little bit, hurts a little more…)
• Frida Kahlo approach – painted portraits of herself with thorns in her neck to describe her pain
- Functional magnetic resonance imaging (FMRI) use enables blood oxygen level dependent (BOLD) signals to detect changes in cerebral activity in patients with neuropathic pain, and this technique allows the study of responses in particular regions of the brain and brain stem.
- Patients with chronic pain show strong activation of the prefrontal cortex, as well as disruption in resting functional connectivity of widespread cortical areas (Baliki et al. 2008).
What are the 4 mechanisms of neuropathic pain?
- increased inflammatory mediators in the CNS/PNS.
- Altered nociceptor activity
- ALtered spinal processing
- Altered central processing (central inhibition)
Describe the role of mast cells in neuropathic pain
• First to be activated
eg) After partial sciatic nerve ligation
• Resident population of mast cells in the peripheral nerve are activated and degranulated at the site of nerve damage
• Release histamine, serotonin, cytokines and proteases
• Histamines seem to be a key mast cell mediators, having sensitized effects on nociceptors and capable of inducing severe burning pain when applied to the skin of patients suffering post-herpatic neuralgia
• The site of primary hyperalgesia is confined to where the injury took place
− Here, tissue damage activates mast cell degranulation
− Histamine binds to receptors on the sensory afferent terminal, sending an action potential
− However, sensory afferents have many collateral branches
− The action potential can travel down the axon, but also down the collateral branch, cuasing substance P release
− This can bind to receptors on mast cells, causing more histamine release
− This can cascade → what started as local injury results in secondary hyperalgesia – the feeling is being perceived in a wide area
- Stabilisation of mast cells by sodium cromoglycate attenuates the development of allodynia
- Treatment with histamine receptor antagonists suppress mechanical allodynia in neuropathic rats
- Direct receptor mediated excitatory effects of mast cell degranulation:
Histamine
• Usually, recordings from nociceptors are silent, unless activated by a stimulus
• Injection of histamine results in them no longer being silent, they have constant activity
• If a noxious stimulus is introduced, gives an amplified signal → hyperalgesia
• This is long-lasting, even when the histamine is taken away, it doesn’t go back to normal
TNFa
• Rapidly upregulated within hours of nerve injury
• Has direct receptor effects → binds to the TNFR1 on sensory neurons, causing an increase in firing rate, and can increase the conductance of TTX-R sodium channels and ATP receptors (P2X) via p38 MAPK → leads to potentiation of nociceptor activity
• Studies show large increase in firing rate from Ad and C fibre afferents post-injection with TNF
• Anti-TNFa (Etancercept) can reduce sensitivity following in vivo nerve injury model
• Anti-TNFR1 can reduce sensitivity
• Hyperalgesia is induced by TNFa injection
So TNF important – the first wave is from the mast cells, the second from neutrophils
Describe the role for neutrophils in neuropathic pain
- Normally, neutrophils aren’t present in nerves
- Following damage, they are the first to infiltrate
- They have a role in phagocytosis
- They increase production of inflammatory mediators, inc. TNF and chemokines, which activate and attract other inflammatory cell types, most notably macrophages → so although neutrophil infiltration is short lived, its effects can be longer lasting through recruitment of macrophages
- Depletion of neutrophils following nerve injury via administration of an anti-neutrophil antibody decreases thermal hyperalgesia
Describe the role for macrophages in neuropathic pain
- Macrophage activation is a central component of Wallerian degeneration distal to axonal injury
- Wallerian degeneration is a process that results when a nerve fibre is damaged, in which part of the axon separated from the neuron cell body degenerates itself distal to the injury
- This is also known as anterograde degeneration
- 2-3 days after nerve injury, resident macrophages infiltrate to the injury site → orchestrated by CCL2 & CCL3 acting on CCR2, CCR1 and CCR4
- They function to phagocytose damage tissue and increase production of inflammatory mediators, eg) IL-1B
- Reducing the number of circulating monocytes via IV liposome encapsulated ciodronoate reduces hypersensitivity
Describe other peripheral inflammatory reactions to nerve lesions (MMPs, neuregulin & ERBB2, NGF and GDNF etc..)
- Activated macrophages and denervated Schwann cells secrete MMPs that attack the ECM → leads to an interruption of the BBB
- Vasoactive mediators including CGRP, substance P, bradykinin and nitric oxide are released from injured axons to cause hyperemia and swelling. These vascular changes support the invasion of circulating immune cells
- Within minutes of a nerve lesion, neuregulin, a growth and differentiation factor present on the axonal membrane, induces activation of the tyrosine kinase receptor ERBB2, which is constitutively expressed on Schwann cells causing demyelination. Later in the course of wallerian degeneration, ERBB2 upregulation and activation is associated with Schwann cell proliferation.
- In the reverse direction, Schwann cells release chemical signals that promote axonal growth and remyelination13. These include NGF and GDNF. NGF and GDNF also directly activate and sensitize nociceptors, contributing to the initiation of pain in response to nerve injury - this can result in persistent pain.
