Physiology of Pain Flashcards
What is Lidocaine/ ligocaine?
- Local anesthetic that acts in the periphery (topically applied to skin)
- prevents nociceptor firing by blocking Na+ channels
What are the three classifications of Pain?
- Nociceptive
- normal functioning of nociceptors
- in response to tissue injury that then subsides
- Somatic vs Visceral
- Inflammatory Pain
- Neuropathic
- pain response to injury to the nervous system
What is Inflammatory pain?
Response of the somatosensory nervous system to tissue damage and inflammation.
- In the periphery, increased inflammatory mediators (cytokines and chemokines) sensitize local nociceptors:
- Lowers threshold for responsiveness (peripheral sensitization).
- Results in activation of pathways (substance p and calcitonin gene-related peptide CGRP) after innocuous input and in exaggerated responses to noxious stimulation. (erythema, heat and sensitisation)
- The plasticity that underpins these changes is rapid (occurring in minutes).
- The inevitable consequence of surgery and tissue trauma.
- Upregulation of nociception normally resolves as wound healing occurs.
What is the difference between the two types of nociceptive pain - Somatic and visceral nociception?
Somatic nociception
- Activation of nociceptors in skin, muscles, bones, joints, and connective tissues
- Transmitted along A-delta and C fibres
- Somatic pain – sharp or dull pain. Exacerbated by movement.
Visceral nociception
- Activation of nociceptors in internal organs
- Transmitted along autonomic fibres
- Visceral pain – poorly localised, deep, squeezing, cramping pain, dull, sickening.
- Associated autonomic symptoms – nausea, vomiting, sweating
Which nerve fibres are involved in pain transmission?
- A-theta fibre: thinly myelinated, medium diameter
- light touch, temperature, nociception
- sharp pricking pain
- C fibre: unmyelinated, small diameter
- temperature. nociception
- slow dull ache/ burning pain
Label the afferent nerve endings in this diagram
Explain nociceptor response to inflammation and tissue injury
- chemicals released as part of tissue injury and inflammation have excitatory effects on nociceptors
- ATP, H+, Serotonin/ 5-HT,
- these activate nociceptors: Purinergic receptors, acid-sensing ion channels, 5-HT3 receptors
- Histamine, Bradykinin, Prostglanding, Nerve growth factor
- ATP, H+, Serotonin/ 5-HT,
Give an overview of the action of nociceptors during neurogenic inflammation
- Activation of one branch of a nociceptor by inflammation triggers the release of substance P and calcitonin gene-related peptide (CGRP) from another
- This causes:
- Vasodilation
- Activation of mast cells –> release of histamine = more inflammation
contributes to the pathophysiology of inflammatory diseases
What is the effect of inflammation on nociceptors?
Exhibit modulatory effects on nociceptors and cause hypersensitivity
- Hyperalgesia: Noxious stimuli producing an exaggerated pain response
- Allodynia: Non-noxious stimuli produce a painful response
Explain the mechanism behind pain hypersensitivity
peripheral and central sensitisation leads to hypersensitivity
Peripheral Sensitization:
- increase in the responsiveness of the peripheral ends of nociceptors
- this is driven by tissue injury
- Bradykinin & NGF: reduce threshold heat-activated channels TRPV1
- Prostaglandins: reduce the threshold of sodium channels
Explain the mechanism of action of bradykinin
Bradykinin indirectly acts on TRPV1
- Bradykinin binds to receptor
- (metabotropic G protein-coupled)
- Activation of protein kinase
- Phosphorylation of TRPV1
Phosphorylation of channel reduces its threshold –> it fires more easily
What is the difference between the fibre classification A-C
- Group A - heavily myelinated
- Group B - moderately myelinated
- Group C - unmyelinated
Where do A-delta fibres synapse?
In the grey matter of the dorsal horn in the Rexed Laminae
→ terminate in Lamina 1 and 5
→ Synapse directly with 2nd order neurones that make up the ascending tracts
Where do C-fibres synapse?
In the grey matter of the dorsal horn in the Rexed Laminae
→ mainly synapse with neurons in Lamina 2 (substantial gelatinosa)
→ synapse indirectly via interneurons (which can be varied)
Explain the role of the Spinothalamic tract with transmission of pain/nociceptors
- pain information ascends the spinothalamic tract
- First-order neurons (nociceptors)
- enter dorsal horn –> form tract of Lissauer –> synapse in substantial gelatinosa
- glutamate and substance P from nociceptors excite second-order neurons
- the A-delta or C nerves synapse with second-order neurons
- the second-order neurone then takes this signal up to the thalamus (via the spinothalamic or spinoreticular tracts).
- third-order neurones project from the thalamus to higher centres.
- descending pathways modulate the signals coming form the ascending pathways
Explain the pathway of second-order neurons
second-order neurons: cross in the dorsal horn at each level and ascend the anterolateral column to the thalamus
What is the role of the Lateral spinothalamic tract?
(new)
- terminates at the thalamus
- ascends anterolaterally in the white matter directly t_o the ventral posterior lateral (VPL) nucleus in the thalamus_
- important in the sensory-discriminative aspect of pain perception
What is the role of the Medial spinothalamic tract?
(old)
- terminates at the thalamus
- this is a polysynaptic pathway that sends projections to the periaqueductal (PAG) grey matter, hypothalamus and reticular system in the midbrain before reaching the medial thalamus
- important in generating the autonomic and unpleasant emotional component of the pain experience
Explain why/ how referred pain occurs
- Convergence of visceral and cutaneous nociceptors on same second-order neurons in the spinal cord
- Brain perceives visceral pain as cutaneous
What is stress-induced analgesia?
- the necessary suppression of pain in order for survival
- battle victims
- endurance athletes
- parturition
Explain the descending regulation of pain
- the Periaqueductal gray matter (PAG) and Rostral ventromedial medulla (RVM) modulate the activity of the spinothalamic tract
- Cortical regions project to PAG –> PAG projects to RVM –> RVM projects to dorsal horn
Explain how pain is inhibited
- Periaqueductal grey matter neurons excite serotonergic neurons, which excite inhibitory interneurons
- Inhibitory interneurons inhibit spinothalamic tract neurons
- inhibit the excitatory effects of nociceptors
What is the role/journey/action of the spinoreticular tract?
- it terminates in the reticular formation of the medulla and pons
- the information then sent to the thalamus
- the thalamus nuclei project diffusely to the entire cerebral cortex where pain reaches the conscious level and promotes behavioural arousal
- spinoreticular tract projects to neurona having a large receptive field that t can cover wide areas of the body and play a role in the memory and emotion component of pain neurons (global overview of your pain experience)
How does the brain create the perception of pain?
- third-order neurons project from the thalamus to the somatosensory cortex
- Primary somatosensory projections: mediate localisation of the pain stimulus
- Secondary somatosensory projections: involved in sensing stimulus intensity
- third-order neurons also project from the thalamus to the limbic system: also the insula and anterior cingulate cortex (ACC)
- Insula (major hub for visceral nociceptive inputs): assessment of nociceptive stimulus intensity
-
ACC: attention and response, also has connections to the Amygdala, hippocampus and hypothalamus
- involved in the creation of emotion, behaviour and memory
Give an overview of the endogenous opioid system
- Opioids play an important role in the inhibition of pain
- E.g. Endorphins, enkephalins
- Opioids are inhibitory
- Act on inhibitory metabotropic receptors
- Released from interneurons at multiple sites
What are NSAID’s?
- examples
- mechanism of action
- these are non-steroidal anti-inflammatory drugs that act in the periphery
- e.g Aspirin and Ibuprofen
- they reduce inflammation by inhibiting prostaglandin synthesis, which reduces peripheral sensitisation
- COX inhibited –> prostaglandin synthesis reduced –> prevents decrease in Na+ channel threshold
Explain the action/ mechanism of Paracetamol
- not an NSAID as it has no anti-inflammatory properties
- acts centrally to reduce clinical pain
- inhibits COX (cyclooxygenase) enzyme in the CNS
- Acts on the descending serotonergic pathway
Explain the action/treatment of Topical capsaicin treatment
- acts in the periphery and is topically applied to the skin
- Acts as a TRPV1 agonist
- persistent opening of TRPV1–> calcium overload –> nociceptor stops working
What are Opioids?
- example
- mechanism of action
- very effective pain relief that acts centrally and peripherally (numerous side-effects)
- morphine, codeine, tramadol
- Acts as an agonist of the endogenous opioid system
- disinhibition in the brainstem
- inhibits channels on nociceptors in the periphery
What is the Gate Control theory?
- Pain evoked by nociceptors can be reduced by the simultaneous activation of low threshold mechanoreceptors (Aβ fibres)
- rubbing or blowing on a painful area can reduce the pain
- Stimulation of Aβ fibres at injury site activates interneurons in the dorsal horn which inhibit spinothalamic neurons
- C fibres inhibit inhibitory interneurons: opens gate
- Aβ fibres activate inhibitory interneurons- closes gate
What is Chronic pain?
- give some examples
- Pain that persists for greater than 3 months
- can be nociceptive or neuropathic
- Chronic back pain, cancer, carpal tunnel syndrome, arthritis,
- fibromyalgia, diabetes, migraine, post-surgery, postherpetic neuralgia (shingles),
- phantom limb pain, multiple sclerosis, trigeminal neuralgia
What is neuropathic pain?
- A lesion or disease of the somatosensory nervous system.
- Impacts on function and causes structure changes in the somatosensory nervous system.
- The result is a combination of sensory loss and increased responsiveness to both noxious and innocuous stimuli.
- Positive phenomena can be described as:
- allodynia (pain after non-painful stimuli)
- hyperalgesia (heightened pain after painful stimuli)
- hyperpathia (an eruptive pain extending beyond the duration of a stimulus)
Give causes of chronic neuropathic pain
- Nerve injury may be a
- compression, traction,
- sever, hypoxia, demyelination,
- tumour or neuroinflammation
- affects 8% of the population
What are the symptoms of neuropathic pain?
- stabbing
- cramping
- burning
- aching
- electricity/ shooting
- hypersensitivity
- constant fleeting and procoked
- in anatomical distribution of nerve supply
Explain the mechanisms of Peripheral Neuropathic pain
- Peripheral sensitization
-
Increased firing of primary afferents
- at nerve injury sites, the damaged tips of nociceptors fire spontaneously - due to the accumulation of transported ion channels at the injury site
- responsible for spontaneous pain and also phantom limb pain
(underlies central neuropathic pain mechanisms)
What are two main mechanisms of Central Neuropathic pain?
-
Central sensitization (within the spinal cord)
- increase in the responsiveness of nociceptive neurons within the CNS - due to a reduced threshold for activation
- Change in activation patterns/ cortical remapping (within the brain)
Explain the mechanism behind reduced threshold for activation and how that causes neurological pain
- Constant firing of axons from the periphery (following injury) –>
- Sustained release of glutamate –>
- Prolonged depolarization of the postsynaptic membrane –>
- Massive influx of Ca2+ through NMDA receptors –>
- Activation of kinases –>
- Phosphorylation of NMDA/AMPA receptors
- Channel protein synthesis
What is Hyperalgesia and Allodynia
-
Hyperalgesia: when activation of nociceptors results in amplified spinal cord activation
- sensations are more painful than they ough to be
-
Allodynia: when non-noxious afferents activate sensitised 2nd order neurons
- non-noxious A-beta fibres also synapse onto 2nd order spinothalamic neurons
What are the key things to consider when managing/ treating chronic pain
- need to treat the patient as individually as possible
- important to manage the primary condition as well as other associated symptoms
- depression
- sleep disturbances
- fatigue
What current neuropathic pain treatment is available
- types of drugs
- Drugs:
- Tricyclic antidepressants (analgesic)
- Anticonvulsants (analgesic)
- Topical capsaicin or lidocaine
- Acupuncture
- Physical therapies – e.g. manipulation of tissues, pacing
- Psychological therapies – e.g. cognitive behaviour therapy
- Surgery – e.g. spinal cord stimulator
What is the action/mechanism of Tricyclic antidepressants
- examples
- they act centrally to reduce neuropathic pain
- Amitriptyline
- Duloxetine
- They act on descending inhibitory pathways to inhibit the reuptake of serotonin and noradrenalin
What is the action/ mechanism of anticonvulsants in treating neuropathic pain
- examples
- act centrally to treat neuropathic pain
- Pregabalin
- Gabapentin
- Carbamazepine
- they work in the spinal cord to reduce excitability by blocking calcium (pregabalin) and sodium (carbamazepine) channels
- Pregabalin blocks nociceptor presynaptic voltage-gated Ca2+ channels
- this prevents the release of glutamate
- pain signal isn’t continued along the spinothalamic tract
What are the NICE guidelines on treating neuropathic pain?
- First-line of treatment:
- Amitriptyline, duloxetine, pregabalin or gabapentin
- Second-line of treatment:
- Switch drugs or combine
- Third-line of treatment:
- Refer patient to a specialist pain service and consider oral tramadol (opioid) or in combination with the second-line treatment consider topical lidocaine
What are the different areas of the nervous system that can cause of chronic pain?
- Peripheral terminals
- Peripheral sensitization
- Axon
- Increased firing of primary afferents
- Dorsal root ganglia
- Changes in protein synthesis
- Dorsal horn/spinal cord
- Central sensitization
- Brain
- Changes in brain activation patterns
Explain Melzack and Wall’s gate control theory
- low- threshold myelinated afferents e.g A-beta fibres (rubbing on the skin) can reduce the response from C-fibre inputs by activating inhibitory interneurons
- non-painful input closes the nerve ‘gates’ to nociceptive input which prevents the AP from travelling up the CNS
What happens in descending inhibitory pathways for pain?
- Originate from supra-spinal structures:
- periaqueductal gray
- reticular formation
- nucleus raphe magnus
- Endogenous opioid receptors are heavily expressed here.
- Serotonin and NA are key neurotransmitters in this pathway.
- Inhibit transmission of nociception at the level of the Dorsal Horn
