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Flashcards in PAIN AND OPIOIDS Deck (25)
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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


Physiological pain

Protects from danger by giving warning about tissue damage


Inflammatory pain

Tissue damage releases pain mediators which cause inflammation and temporary hypersensitivity
- Also cause allodynia and hyperalgesia


Neuropathic pain

Somatosensory nervous system lesions which cause permanent hypersensitivity and pain doesn’t subside
- Also cause allodynia and hyperalgesia


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


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


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


Bipolar neurons

- Carry pain information from periphery to dorsal horn
- Three different neurons carry this information: C-fibre, Abeta-fibre and Adelta-fibre


C fibre

- Unmyelinated
- Carry stimulation from skin, deeper tissue and muscle
- Are thermoceptors, mechanoceptors and nociceptors


A beta fibres

Myelinated and carry information of low intensity stimuli - for example during allodynia
- Are mechanoceptors


A delta fibres

- Myelinated
- Allow transmisson of sharp sensations and acute pain
- Mechanoceptors and nociceptors


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


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


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


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



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


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


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


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


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


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


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


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


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


Mechanism of opioid dependence

- Opioid receptors get desensitised
- Increases adenylyl cylase activity
- Increase Na release which causes withdrawal symptoms