Lecture 9 - Sensation and sensory processing, pain Flashcards
Give an overview of the organisation of the nervous system
- Incoming stimulus is revieced by the sensors - sensory receptors in the PNS
- Afferent neurons from the sensory receptors synapse onto interneurons in the integrating centres in the CNS(varies: brain - human, ganglion - squid)
- Interneurons in the integrating centres synapse with efferent neurons which synapse onto effector organs (muscles, glands) in the PNS through output pathways to result in a response
- feedback from PNS to the integrating centres
How is the basic plan of the organisation of behaviour in the nervous system variable?
Difference in the distribution of the integrating centre, CNS or in distributed ganglia
What is sensation and what does it involve?
Sensation involves the ability to transduce, encode, and perceive information generated by stimuli arising from both the external and internal environment
What are the types and examples of input stimuli of the NS?
Mechanosensation -touch, movement, imbalance, sound Thermosensation -temperature Photosensation -light Nociception (combination of a number of sensations [mechanosensation, chemosensation, thermosensation] -pain Chemosensation -taste, smell, moisture (also osmosenasation)
What is the anatomy of detection of incoming stimuli?
Have either dedicated organs or dispersed receptors
- tuned to life strategy of an organism
e. g. - mouse mixture of chemosensation and mechanosensation
- insect mostly chemosensation
What are the features of TRP channels?
- superfamily of ion channels
- found across phyla
- often have conserved role
- six transmembrane domains (with varying regions of homology)
- intracellular and extracellular structures change and are subject to modulation
- characterised by a conserved TRP domain
- permeability to cations
- single channel can be activated by disparate mechanisms
- critical roles in responses to all major classes of external stimuli
- expressed in sensory neurons
- work as heteromultimers in supramolecular complexes (channelosome)
What is TRPY?
- found in yeast (aka not in neurons)
- required for osmotic resisitance
What is TRPML?
- expressed globally and localised in lysosomes
- mutations give risse to the childhood neurodegenerative disease ‘Mucopolysaccharidosis IV (MPS IV)
- where lysosomes do not function well and ‘store’ undegraded material
What is a channelosome?
-when the intracellular and extracellular domains of TRP channels bind to other proteins to generate a complex that can be important to function
What can TRP channels be gated by/
- many endogenous and exogeneous ligands
- conformational change (temperature, mechanical)
- Ca2+ status (acts as a store operated Ca2+ channel)
What is nociception?
The sensation of pain
-purely physiological
What is the role of nociception?
To alert to impending injury or to trigger appropraite protective response
-transduction of noxious stimuli (thermoceptive pain, mechanoreceptive pain, chemoreceptive pain) and the cognitive and emotional processing
Where is the sensory modailty of nociception located?
PNS
CNS
ANS
What are nociceptors?
A class of neuron (proposed by Sherrington) activated by stimuli capable of causing tissue damage.
What is hyperalgesia?
increased sensitivity to pain, usually associated with injury
What is the circuitry of primary sensory neurons involved in nociception in the PNS?
primary sensory neurons in the dorsal root ganglian project dendrites to peripheral tissue
What are the two types of primary sensory neurons involved in nociception in the PNS?
C Fibres
Aδ Fibres
(type I and II - mechanosensitive, mechanothermal)
-have morphological and physiological differeces
-both express the vanilloid receptor (VR1 or TRPV1)
-respond to rises in temperature and capsaisin and extracellular acidification
What are the features of Aδ fibres?
- fast, compared to C fibres (20m/s)
- two classes, mechanosensative and mechanothermal
- express the vanilloid receptor (VR1 or TRPV1)
- respond to rises in temperature and capsaisin and extracellular acidification
- causes the immediate response to pain
- lightly myelinated
What are the features of the C fibres?
- polymodal
- express the vanilloid receptor (VR1 or TRPV1)
- respond to rises in temperature and capsaisin and extracellular acidification
- major nociceptive receptor due initally to heat, then to acidification due to inflammation giving rise to longer term responses (heat has two componants, fast pain and slow pain)
- mediate slow, burning pain
What are other A fibres (aside from Aδ fibres) and what are their features?
Aβ (touch) Aα (proprioception) -large diameter (linked to high speed of conductance) -myelinated neurons -reponsive to non-nociceptive stimuli -very fast response
What are other C fibres, not involved in the slow pain response, and what are their features?
Ultra-slow histamine selective fibres -covey itch (pruritogenesis) Tactile C-fibres -low threshold fibres responding to sensual touch CT fibres found in hairy skin C-mechano- or metabo-receptors -muscle cramp and fatigue
How can nociceptors be cross modal and what does this mean?
e. g. -activated by multiple simuli (thermosensitive and chemosensitive)
- by expressing multiple TRPs
- but when activated perception is the same (Labelled line theory)
What is the labelled line theory?
Pathways carrying sensory information are specific for one stimulus
What is an alternative to the labelled line theory and what is this?
Pattern theory
- some sensory systems (esp. taste and olfaction) integrate information across multiple primary afferents
- some types of primary afferents are multi-modal (more than one snesation can be evoked b activation)
- an ascending pathway can convey sensory information by altering the temporal pattern of action potentials among multiple primary afferents
- Pattern of activation forms the basis of perception
In what structures do the nociceptive neurons arise?
The dorsal root ganglion
What is the order of response to nociceptive stimuli?
1-reflex withdrawal
Followed by higher order behavioural responses
What is the capsaicin receptor?
TRPV1
What is capsaicin?
The active ingrediant of capiscum or chilli peppers, produced by plants to prevent ingestion, a mechanism to protect seeds
-vanilloid
What is the strength of capsaisin measured in?
Scoville units
e.g. jalepeno 5,000 schoville units
habernero 300,000 schoville units
How was the TRPV1 capsaisin receptor identified and its function found?
-expression cloning of the receptor by Caterina (1997)
-KO mice used to identify the in vivo function of the receptor, Caterina (2000)
FOUND
-Mice lacking TRPV1 are deficient for vannilois ellicited pain, thermal sensation and tissue injury induced thermal hyperalgesia
What can TRPV1 activity be modulated by (both inhibition and stimulation) ?
- capsaisin (similar structure to anandamide but acts antagonistically to stimulate the TRPV1 channel)
- anandamide (inhibits activity TRPV1 )
- heat >43*C (activates)
- camphor (activates)
- piperine (activates)
- garlic (activates)
What is anandamide?
An endo-cannabinoid (shuts off TRP channels)
What is the relationship between anandamide and capsaisin?
- Anandamides inhibit TRPV1 receptors
- Capsaicin has strucutral similarities and can bind to the same sites to antagonisically stimulate the channel
- channel normally gates at >42*C
- when capsaisin bound gates at 37*C
Why might plants have evolved the synthesis of chemicals such as capsaisin and pipericin?
To subvert the function of nociceptors and protect their seeds from ingestion
What synthetic molecules might be possible to use as an analgesic?
Synthetic amandamide mimics
What ligands can a TRPV1 channel be activated and sensitised by?
Activated
-acidification near the outer pore region
-double knot toxin from the Earth Tiger tarantula (locks pore into open configuration)
-capsaisin (lowers the temperature of activation from 43 to 37)
Sensitised
-signal transduction mechanisms (on cytoplasmic loops) e.g. Ca2+, PKA, PLC, PIP2,
If activated by any the sensory effect is the same (pain-activation results in activation and neuronal stimulation)
Why is the sensation of acidifcation by TRPV1 important?
Damage and the inflammatory soup
-long term perception of pain (hyperalgesia)
How does injury cause longer term activation of nociceptors by sensitisation?
Through damage and the ‘inflammatory soup’
-injury has an initial stimulus causing an immediate response, followed by a longer term sensitisation of the injury site mediated by sensitisation of some of the same TRP channels that transduced the original response
- Damage recruits an immune response (cells of the immune system and an inflammatory response)
- an increase in blood flow (heat pressure)
- acidification, reactive oxygen species
- TRPA1 sensitive to: ROS, chemical irritants, products of tissue injury and inflammation, G-proteins activated by bradykin receptors, raised calcium (activation of TRPV1)
- leads to a sensitized response to nociception
What is TRPA1 involved in, activated by and sensitised by?
Involved in the ‘inflammatory soup’ and the longer term actvation of nociceptors by sensitisation
Activated by:
-ROS
-chemical irritants, particularly products of tissue injury and inflammation
Sensitised by:
-G proteins activated by bradykinin receptors
-raised calcium (from activation of TRPV1)
What is TRPA1 in insects?
a mechanosensor
-if TRPA1 is a mechanosensor, then inflammation caused by injury will produce pressure potentially contributing to TRPA1 activation
What is the pathway involved in nociception?
Afferent nociceptive fibers (first order neuron) synapse to the dorsal horn (spinal cord)
- DH nociceptive fiber (located in the periphery) = second order neuron
- cells in the dorsal horn are divided into physiologically distinct layers, different fiber types form synapses in different layers
- after first order neurons synapse with specific structures in the DH the second order neurons send their information via the anterolateral system to the thalamus
- information is then processed in the ventral posterior nucleus and sent to the cerebral cortex in the brain
Are nociceptive neruons dynamic or stable?
Dynamic
-constantly changing over time
Where can modulation of the sensory system occur?
- modulation in the dorsal horn of the spinal column
- at higher levels of communication between second order neurons
- or can feed down through descending inhibitory pathways to affect local circuits by the modification of primary neurons (alters responses of reflex circuits)
- Descending system alters responses of reflex circuits
What are involved in thermosensation?
-non-nociceptive thermosensory neurons
What are the features of thermosensory neurons?
- rapidly conducting
- the tuned sensitivity of TRP channels to ranges of temperatures ensures efficient detection across a range of temperatures for thermosensation
What fibres express both TRPV1 and TRPA1 channels?
C-fibres in the periphery
What is the first site of sensory integration?
the stratification within the dorsal horn of the spinal column
- major input to the CNS
- represents second order processing, immediate response and modulation of a signal
Give an experimental example of second order structures as the site for stimulus integration
Coding of temp in the drosophila brain
- Identification of TRP channels reacting to cold and warm temperature identified
- expression patterns showed similar distribution patterns in the antennae sending projections to neighbour glomeruli
- Glomeruli are second order structures that integrate information
