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 two classifications of Pain?
- Nociceptive
- normal functioning of nociceptors
- in response to tissue injury
- Neuropathic
- pain response to injury to the nervous system
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
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
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
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 activity of 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
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
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
- burning
- aching
- electricity/ shooting
- hypersensitivity
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 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 int he responsiveness of nociceptive neurons within the CNS - due to 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
