Pain physiology and analgesic therapies Flashcards
What is pain?
International association for the study of pain (IASP): Pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.
- A personal experience that is influenced to varying degrees by biological, psychological, and social factors.
- Pain and nociception are different phenomena.
- Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being.
A first characterization of pain types…
ACUTE pain can be intense and is mostly short-lived. In
most cases it indicates tissue damage and/or an injury.
CHRONIC pain last much longer compared to acute pain. Mild and severe forms are known.
Classification of pain (according to involved structures)
Nociceptive pain (acute pain) is caused by stimulation of nociceptors, a set of specialized peripheral nerve cells.
-> SOMATIC pain is associated with the skin, skeletal muscles, bones, joints, fibers.
Stimuli: chemicals, temperature, mechanical stress.
-> VISCERAL pain develops in the thorax (chest, abdomen, back…).
Stimuli: insufficient blood supply, inflammation.
-> NEUROPATHIC pain (nerve pain) is known as pinched or trapped nerve pain.
Causes: nerve degeneration (e.g. stroke, multiple sclerosis, insufficient blood supply, specific gene mutations), nerve infection, acute pain may turn into neuropathic pain
-> SYMPATHETIC pain involves damage of sympathetic nerves which control blood supply and sweating of the skin.
Causes: Soft tissue injuries.
Other forms of pain are phantom pain (amputation), psychogenic pain (mental and emotional factors e.g. hypochondriasis) or breakthrough pain (e.g. in cancer).
Pain-related peripheral structures
-> NOCIRECEPTORS are primary sensory neurons, which are activated by stimuli capable of causing tissue damage. Characteristic thresholds or sensitivities distinguish them from other sensory nerve fibers.
-> Nociceptive nerve endings are not myelinated; they contain TRANSDUCTION PROTEINS that translate noxious stimuli into electrical signals.
DRG (dorsal root ganglia)
- pseudo unipolar neurons
- pain signaling
- fast (5-50 m/s) Ad fibers and slow (1 m/s) C fibers (first and second pain phenomenon)
- thin layer, non myelinated axons respond to noxious stimuli
- contains interneurons respond to noxious, non noxious stimuli (modulation of sensory input)
- interneurons respond to signals from Beta fibers
- thickest layer respond to non noxious input
- contact to layer II respond to signals form Abeta, Agamma, C fibers
-> different kinds of nociceptors detect different kind of pains
Hyperalgesia
-> Increased sensitivity to noxious stimuli (sensitization of nociceptors; amplification of the signal) as the consequence of tissue damage (e.g. after stroke), irritants (e.g. in the periphery), inflammation
* Inflammatory or allergic response
* Dysregulation in the brain and/or nociceptors
* Involves immune cells
* Severe forms
-> Treatment with e.g. Gabapentin, NMDA antagonists (e.g. Dextromethorphan, also opioids like Methadone and others)
-> side effects: learning/memory deficits, psychosis, ataxia.
Allodynia
-> Non-noxious signals cause pain by indirect activation of nociceptors
-> Fast adapting Ab fibers gain access to nociceptors and activate them (hypothesis: neurochemistry of GABA changes at the gate from inhibitory to excitatory)
* Causes: nerve damage, injury in the spinal cord
* Mechanosensitive and nociceptive fibers may contact the same interneurons in the dorsal horn -> wrong input causes pain (e.g. sunburn)
-> Treatment depends on type: opioids, NaV channel blockers (LA)
Peripheral pain signaling depends on ion channels
- PERIPHERAL TERMINAL
Transduction of noxious stimuli into an electrical signal
Specialized transducer proteins recognize heat / cold, chemicals or mechanical stimuli. - DORSAL ROOT GANGLION
Propagation of the signal
Voltage-gated ion channels generate action potentials and support their propagation along the axon. - SPINAL CORD
Synaptic transmission
Transmitter-activated ion channels.
-> Nav 1.8 and and Nav 1.9 are also implicated in human pain perception
Transduction channelopathies observed in mice
TRPs: TRPV1, TRPV4, TRPM 8, TRPA1
ASICs: ASIC 1, ASIC2, ASIC3
P2XRs: P2X3, P2X4, P2X7
Ion channels involved in transduction
- TRP: Transient Receptor Potential
- TRPV1 senses moderate heat threshold 43 °C
- TRPV2 senses noxious heat > 50 °C
- Non-selective cation channel
- C fibers and type-II Ad fibers
- ASIC: Acid-Sensing Ion Channel
- Widely expressed in the CNS and the PNS
- ASIC1a/b, ASIC2a/b and ASIC3 are proton gated (pH0.5 5;
suggestive of Glutamate or Aspartate dependence), ASIC4 not - Touch sensation, inflammatory processes
- P2X: Purinoreceptor
- Seven members: P2X1-7 , 500-600 aa, gated by extracellular ATP
- Homo- and heteromers
- Active in damaged and inflamed tissue (50 μM – 5 mM ATP)
- Expressed in C fibers
Inflammation causes pain
Inflammatory mediators (IMs) released from cells during tissue injury sensitize nociceptors
* Bradykinin, H+, 5HT, ATP, Neurotrophins (nerve growth factors), Leukotrienes, Prostaglandins (PGE2, PGI2) are the most important IMs
* Some IMs interfere directly with ion channels; others use different pathways to sensitize nociceptors
Fever is part of the inflammatory response
* Tissue damage, inflammation, transplant rejection or malignancy enhance the levels of Cytokines (e.g. IL-1β, IL-6, TNF-α) and Interferons which act as endogenous pyrogens
* PGE2 is one of the main triggers of fever; it can cross the blood-brain-barrier and stimulate EP3 (and possibly also EP1) receptors that are exposed on neurons involved in temperature regulation
Transduction phenotypes are treated with COX inhibitors
Receptors IP, DP1, EP2 and EP4: via Gs-mediated increase in cAMP
Receptors EP1, FP and TP: via Gq-mediated increase in Ca2+
Receptor EP3 via Gi-mediated decrease of cAMP
Transduction phenotypes are treated with COX inhibitors
-> Acetylsalicyclic acid (ASA, Aspirin)
Acetylsalicylic acid (ASA, Aspirin)
* T1/2 = 20 min
* Rapidly deacetylated to salicyclic acid (SA) which has a T1/2 of 2-3 h
* Protein binding: 50 – 70% for ASA and 70 – 98% for SA
* Acts via COX-1/2 inhibition
* Permanent platelet inhibition (COX-1)
* Clotting time increases
Transduction phenotypes are treated with COX inhibitors
-> Dicophenac
Diclophenac (acetic acid derivative)
* T1/2=1.2–2h
* Protein binding: 99%
* Acts via COX-1/2 inhibition
* First-pass effect
* Oral availability 50%
* More potent as ASA
Transduction phenotypes are treated with COX inhibitors
-> Ibuprofen (propionic acid derivative)
Ibuprofen (propionic acid derivative)
* T1/2=2–4h
* Protein binding: 99%
* Acts via COX-1/2 inhibition
* As potent as ASA
Transduction phenotypes are treated with COX inhibitors
-> Paracetamol (para-aminophenol derivative)
Paracetamol (para-aminophenol derivative)
Not a classical NSAID, i.e. no anti-inflammatory activity !
* T1/2 = 2 h
* Protein binding: 20 – 50%
* Seems to prefer COX-2 over COX-1
* Almost no effect on platelet aggregation
* As potent as ASA in terms of analgesic activity
