Lec 8- Analgesia I Flashcards
1
Q
Pain, an unmet medical condition
A
- How is pain sensed and transduced
- How do analgesics act on the pain-transducing pathway to produce pain relieving effect
2
Q
The nociceptive pathway
A
- Nociception: the neural process by which noxious stimuli are detected and processed by the sensory nervous system, leading to the perception of pain
- Nociception is not the same as pain experience
- Pain has sensory and emotional components, requiring consciousness
- Nociceptors detect: thermal, mechanical and chemical stim
- The brain can send an inhibitory signal to block pain
3
Q
Pain classification- Pain duration
A
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Pain duration
- Acute pain: <3-6 months. Tissue injury, trauma, childbirth
- Chronic pain: >3-6 months, outlast tissue injury
- Hyperalgesia: enhanced pain responses to noxious stimuli, due to sensitization of peripheral nocicpetors by chemical mediators (e.g. PG bradykinin). For example heat, cold, mechanical hyperalgesia
- Allodynia: pain caused by innocuous stimuli. Example, mechanical or thermal allodynia
4
Q
Pain classification 2. causes of pain
A
- Nociceptive pain: direct activation of pain fibres by noxious stimuli
- Inflammatory pain: inflammatory mediators
- Neuropathic pain: damage to the somatosensory nervous system
5
Q
The nociceptive pathway
A
- 3 main component
- Peripheral component: Nociceptors and afferent neurones (A-delta and C)
- Spinal cord: DRG, this part transmitts signals from peripheral to brain and vise versa
- Central: brain de-code pain signal from peripheral
6
Q
Nociceptive pathway- nociceptors
A
- TRPV1: heat activated ion channels, also activated by capsaicin, H+ ions (pH <5.5), permeable to Na+, Ca2+
- TRPM8: cold-activated ion channel, also activated by menthol
- TRPA1: detecting noxious cold and mechanical stimuli, oxidative stress, lipopolysaccharide (LPS), irritating chemcials (e.g. AITC from wasabi, mustard, cinnamon)
- TRPV4: sensing hypo-osmolarity, arachidonic acid metabolites
- ASICs: (Acid-sensing ion channels): activated by acid (pH <6.4)
- P2X3: ATP-gated ion channels
- Mechanically activated ion channels: ENac, PIEZO
- Nociceptors function like pain signal generators that convert damaging stimuli into nociceptive signals
7
Q
Nociceptive pathways- inflammatory mediators
A
- During tissue injury, many inflammatory mediators (bradykinin, histamine, PGs etc) can stimulate nociceptors to produce a pain response
- The nerve in turn can release inflammatory neuropeptides (substance P), can activate mast and other inflammatory cells to potentiate the inflammatory and so pain response (positive feedback)
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8
Q
Inflammatory mediators and metabolites
A
- Bradykinin: generated in damaged tissue, coupled to B1 and B2 receptor, sensitizes TRPV1, TRPA1 and TRPV4 via activating PKC
- Prostaglandins E+F: increase excitability of afferents by acting on Na+ and K+ion channels, and sensitizing TRPV1,4 via activating PKA (cox inhibitors- inhibit PG)
- NGF (nerve growth factor): sensitizing TRPV1, Na+, K+ channels, increasing the expression of these ion channels, released from damaged, inflamed tissue and cells
- Metabolites: Acid, ATP, 5-HT, histamine etc. Released from damaged cells
- Neuropeptides: Substance P and calcitonin gene-related peptide (CGRP) released from afferent nerve fibres. Bidirectional signalling
9
Q
Nociceptive pathway- afferent nerve fibres- A-delta fibres vs C fibres
A
- Pain signals from nociceptors are transmitted by afferent nerve fibres to the brain
10
Q
Transduction of nociceptive signals
A
- Fibres act first to give a rapid pain response
- C fibres will then follow with a longer lasting, slow, dull pain
- If you block A fibres you block sharp pain
- If you block C fibres you block persistent pain
11
Q
Nociceptive pathway- spinal cord
Termination of afferent nerve fibres in the spinal cord
A
- afferent nerve fibres carry nociceptive signals into the spinal cord
- This shows how spinal cord forms layers with different nerve fibres terminating in the different layers
- Most pain nerves terminate in the superficial layers of the dorsal horn
12
Q
Nociceptive pathway- spinal cord-
A
- Nociceptive signals can be modified= pain enhancement or inhibition
- The spinal cord can form pathways with both afferent fibres (pain) or interneurons (inhibit pain)
- Afferent= glutamate= stimulation
- Interneurones= GABA= Inhibition
- Shows spinal cord is not just a relay system but can actually modify pain signal for enhancement or inhibition
13
Q
Gate control theory
A
- Spinal transmission (T) neurones receives input from nociceptors to evoke nociception
- T neurones concurrently receive other innocuous inputs from A-beta fibres, which also activate inhibitory interneurons in substantia gelatinosa (SG) to reduce nociception
- Gate control theory: inhibitory neurones (yellow) SG determine whether nociceptive input from the peripheral would be relayed through the spinal transmission system (red, T) to higher CNS areas where pain is conciously perceived
14
Q
Wind up
A
- Wind up is a progressive, frequency-dependent facilitation of the responses of a neuron evoked by repetitive (Usually electrical) stimuli of constant intensity
- Rat paw inflamed with UV light, stimulate afferent fibres and record electrical activity in spinal cord neurons
- Wind up was developed after repetitive stimulation
- Post synaptic responses are reduced by NK-R and NMDA antagonists
- The system is therefore sensitized and is hyperalgesic
15
Q
Spinal mechanism of wind up
A
- Wind up (central sensitisation)- pain responses increases over time in response to repetitive stimuli
- Occurs in dorsal horn neurons
- Caused by inputs from peripheral nocicpetive C fibres, leading to increase excitability of dorsal horn neurons
- Glutamate (NMDA) and neurokinin NK1 receptors are required to generate wind up. Antagonists for NMDA and NK1 receptors can thus block wind up
- Opioids and NSAIDs can also reduce or abolish wind up
16
Q
Central modulation of pain- descending pain inhibtory pathways
A
- Ascending pain signals activate PAG, NPRG and then NRM nuclei in the brain
- Activated NRM releases 5-HT, enkephalin to inhibit pain process in the spinal cord
- Negative pain modifying loop;
- Opioids increase PAG, NRPG activity
- Opioids decrease afferent and spinothalamic neuron excitability
- This is a negative feedback when the brain is constantly stimulated this can kick in to inhibit pain signals
- NB- PAG = PeriAquaductal Grey
- NRM = Nucleus Raphe Magnus
- NRPG= Nucleus Reticularis ParaGigantocellularis
- LC = Locus Coeruleus
17
Q
Phantom limb
A
19
Q
Opioid receptor
A
- 3 major receptor subtypes
- Mu (u)
- Delta (D)
- Kappa (k)
- 7-trans membrane domains
- G-protein linked
- Evidence for further subtypes (sigma (S)) and subtypes within each group
- Inhibit transmission release
- Inhibit neuronal excitability
20
Q
Opioid receptor mediated effects
A
