Flashcards in PAIN AND OPIOIDS Deck (25)
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1
What is pain?
- Induced in response to tissue damage
- Due to mechanical or chemical stimulation
- Muscoskeletal/ rheumatic pain and neuropathic pain are the most common form
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Physiological pain
Protects from danger by giving warning about tissue damage
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Inflammatory pain
Tissue damage releases pain mediators which cause inflammation and temporary hypersensitivity
- Also cause allodynia and hyperalgesia
4
Neuropathic pain
Somatosensory nervous system lesions which cause permanent hypersensitivity and pain doesn’t subside
- Also cause allodynia and hyperalgesia
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Allodynia and hyperalgesia
Non noxious stimuli which evokes pain and wouldn’t normally do this is allodynia
Hyperalgesia is a noxious stimula which evokes pain
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Pain pathway
- Bipolar neutrons has two projections - one in superficial layer and one in peripheral
- Activates peripheral nociceptors
- Cell body found in dorsal root ganglia
- Substance P and Glutamate activate Neuron and transmit pain information
- information from both spinal cord reaches the sensory cortex via the thalamus
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Synaptic endings
Packed with pain receptors as well as histamine and serotonin receptors
ATP also acts as a neurotransmitter for purinergic receptors - P2X3
- Tissue damage causes cell death and the release of its content which consists of a lot of ATP
8
Bipolar neurons
- Carry pain information from periphery to dorsal horn
- Three different neurons carry this information: C-fibre, Abeta-fibre and Adelta-fibre
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C fibre
- Unmyelinated
- Carry stimulation from skin, deeper tissue and muscle
- Are thermoceptors, mechanoceptors and nociceptors
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A beta fibres
Myelinated and carry information of low intensity stimuli - for example during allodynia
- Are mechanoceptors
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A delta fibres
- Myelinated
- Allow transmisson of sharp sensations and acute pain
- Mechanoceptors and nociceptors
12
Gate control theory
Substantia gelatinosa packed with small inhibitory neurons
- Extend from SG to synapse
- Activated by pain stimulation in spinal cord
- Takes place in order for pain to subside
- A beta fibres activate SG
- GABA and opioids are inhibitory neurotransmitters
13
Descending pathways
- Inhibit transmission of pain information
- Neuron from dorsal horn acts on neurons in raphe nucleus of brain which get activated by 5-HT
- Enkephalin neurons run to dorsal horn and block pain transmission
- PAG area of brain contains opioid receptors which activate neurons in raphe nucleus activating descending inhibitory neurons
- NAergic neurons from locus coeruleus directly to dorsal horn release noradrenaline which blocks pain
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Activation of bipolar neurons
- Packed with nociceptors
- Binding of glutamate or substance P opens Na+ channel
- Contains sodium and potassium channels in order to depolarise the neuron
15
Neuropathic pain
Caused by lesion of somatosensory nervous system I.e. diabetes, stroke, MS, aging, major surgery/trauma
- Hyperexcitability of bipolar neuron causes release of substance P and glutamate which activate receptors
- Na+ and Ca2+ influx causes depolarisation
- Hyperexcitation causes endocytotoxicity causing cell death and further lesions
16
Plasticity/hyperpolarisation
1.) Activation - NMDA receptor sensitised
2.) Modulation - phosphorylation of NMDA receptor due to constant glutamate release and continuous receptor activation
3.) Modification - Gene expression altered and release of NT increases or decreases. Altered sensory nerve phenotype causing change from C fibre to A fibre
17
Pharmacotherapy for neuropathic pain
1.) TCA’s (tricyclic antidepressants) e.g amitryptiline which inhibits NA reuptake
2.) Anti-epileptic e.g Carbamazepine which acts on voltage-gated Ca2+ channel reducing excitibilaty of sensory neuron
3.) Anti-epileptic e.g. Gabapentin and Pregabalin which binds to alpha 2 delta subunit of L-type voltage- gated ca2+ channel reducing Ca2+ influx and reducing excessive neurotransmitter release
18
What is an opioid by definition?
Endogenous or synthetic substance which has morphine-like effects and is antagonised by naloxone
- These effects are analgesia, respiratory depression, euphoria and sedation
19
Opioid receptor function
- GPCR 7 transmembrane proteins
- Coupled to Gi
- Inhibits adenylyl cylase
- Reduces cAMP and PKA
- K+ channels open causing hyperpolarisation and reduces neuronal excitability
- Reduces opening of calcium voltage gated channels reducing calcium influx and reducing release of neurotransmitter
- Found in pain regions such as PAG and thalamus as well as dorsal horn
20
Dorsal horn opioid receptors
- Found pre synaptically which inhibit release of substance P and glutamate
- Found post synaptically causing hyperpolarisation of neuron
- Activates descending inhibitory neurons as there are opioid receptors in PAG
21
Pharmacological effects of opioids
- Analgesia mainly by mulle
- Given in high doses can cause respiratory depression as the neuron which detects CO2 in the brain is blocked
- Causes constipation by reduced gastric motility
- Causes euphoria and sedation
- kappa causes dyspepsia
- Causes nausea and vomiting and CTZ is packed with opioid receptors
22
Tolerance of opioids
Meaning same repeated dose begins to have low pharmacological activity
- Opioid binds to receptor and opens K+ channel causing hyperpolarisation causing analgesia
- G-receptor kinase phosphorylates receptor causing desensitisation
- Activated arrestin
- Causes tolerance
- Opioids do not down regulate receptors except methadone
23
Synthetic opioids
- Diamorphine - analgesia for tissue injury and tumour growth
- Pethidine - Used in labour as it doesn’t reduce uterine contractions
- Fentanyl is lipophilic so rapid onset but shorter duration than morphine
- codeine helps with mild pain
- Tramadol is an opioid agonist and a weak NA reuptake inhibitor
24
Euphoric effects of opioids
- Part of Mesolimbic pathway where neuron projects from ventral tregmental area to nucleus accumbens
- GABA interneurons in VTA
- Normally, GABA interneurons release GABA which bind to receptor and inhibit release of Dopamine at nucleus accumbens
- When opioid is present it binds to receptor on GABA interneurons inhibiting release of GABA and as a result stimulates release of dopamine which causes euphoria
- Opioid disinhibition effect
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