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What is pain? (IASP definition; International Association for the Study of Pain)

Unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.


What is nociception?

The neural physiological process of encoding and processing noxious (painful) stimuli; bare physiological aspect of pain.


Describe the basic nociceptive pathway.

1.) Nerve endings innervate skin re. injury/pressure/temperature/pH
2.) Nociceptor carries signal to dorsal root/spinal cord
3.) Projection neurone to brain relays noxious stimuli.


What is a nociceptor and what is its structure (type of neurone, location of cell body etc)?

- The sensory neurone detecting noxious input
- A pseudounipolar neuron with a peripheral and central axon. Cell body lies in the dorsal root ganglion.


What is meant by a pseudounipolar neurone?

Cell body has one projection (uni) that splits/branches into two; a peripheral axon to the nerve endings and a central axon to the central terminal.


What is the structure of a nociceptor nerve ending and what stimuli do they detect?

- Bare; no myelin just exposed nerve fibre
- Detects high threshold noxious stimuli such as: heat & cold, high threshold mechanical stimuli e.g. hammer blow, certain chemicals e.g. capsaicin in chili.


How do nociceptor nerve endings detect their stimuli?

Specific cation channels detect stimuli; changing membrane potential upon activation and leading to an AP i sufficient stimuli.


What is TRPV1 and what does it do?

- A multi-modal receptor for capsaicin, protons (acid) and noxious heat
- Stimuli opens channel leading to Na+/Ca2+ influx
- Depolarising membrane leading to AP if sufficient grading


What is the structure of TRPV1 and which part conveys cation selectivity?

- 4 subunits form an ion channel
- Each subunit consisting of 6 TM helices with a pore-forming loop
- P-loop between Helixes 5 & 6 (that form the basis of the pore) conveys selectivity for Na+ and Ca2+


What other TRP channels are there and what do they detect?

- TRPA1; garlic/horseradish/cinammon; 0 degrees
- TRPM8; mint
- TRPV3; camphor
- TRPV1 (as before; chili etc)
- TRPV2; 60 degrees

Signal translated to AP.


What are the 2-3 steps of an AP at the peripheral terminal?

1.) Transducer potential; noxious stimuli transduced to membrane potential
2.) Generator potential; changes in membrane potential building up to threshold potential
3.) AP fires and sends signal towards spinal cord


What voltage-gated sodium channels (VGSCs) are present in the nociceptor and how are they classed?

Tetrodotoxin sensitive:
- NaV1.1, NaV1.6, NaV1.7
- Clinical pain role

Tetrodotoxin insensitive:
- NaV1.8, NaV1.9


What roles do VGSCs play with nociception; differences between tetrodotoxin sensitive and insensitive?

Tetrodotoxin sensitive:
- Key role in acute noxious mechanical sensation

Tetrodotoxin insensitive:
- Role (lesser) in acute noxious mechanical sensation
- Acute cold sensation; NaV1.8 does not inactivate at lower temperatures whereas all other NaVs do.


What are the structural differences between nociceptive nerves and proprioceptive nerves, and what does this mean?

Aδ fibres;
- lightly myelinated
- medium diameter

C fibres (slowest);
- unmyelinated
- small diameter

Proprioception (light, touch - v fast);
Aβ fibres;
- myelinated
- large dianeter


Describe what happens at the (presynaptic) central terminal when an AP arrives.

1.) APs picked up by VGCCs (e.g. CaV2.2), ion channels open
2.) Ca2+ influx into nerve terminal
3.) The NT glutamate (and substance P) is packed into vesicles and released into the synaptic cleft


Describe the events at the postsynaptic membrane at the central terminal with an AP.

1.) NT (Glutamate) travels across cleft and binds to AMPA receptors
2.) AMPA = ligand (glutamate) gated ion channel; channels open allowing Na+ influx
3.) Depolarisation occurs and AP transmission into spinal cord


Other than AMPA, what other glutamate receptors are present on the postsynaptic membrane?

- NMDA receptors (NR1-3)
- Kainate receptors (GluR5-7, KA1,2)
- Metabotropic receptors (mGluR1-8)


How do the Metabotropic receptors mGluR1-8 differ from the other glutamate receptors?

- AMPA/NMDA/Kainate; ligand gated ion channels
- mGluR1-8; transmembrane receptors resulting in Phospholipase C activation or Adenyl cyclase inhibition (depending on subtype)


When are NMDA/mGluR1 activated aside from the principle AMPA?

After sustained glutamate release


Where is nociceptor activity most associated with in the spinal cord?

Dorsal horn; Layer I and II.
(Ventral horn mostly motor activity)


What are the two classes of nociceptor connections in the spinal cord?

- Projection neurones (direct to brain)
- Interneurons (relay neurones)


What types of interneurons are there?

- Inhibitory (GABA)
- Excitatory (Glutamate)


Are nociceptive inputs just directly connected to projection neurones to the brain?

No; input from nociceptors (Aδ, C) engages a network of neurones; with fibres leading to the projection neuron, and interneurons (excitatory or inhibitory).


What happens to the nociceptive input after going through the superficial dorsal horn?

- AP goes via projection neuron to the thalamus, innervating the somatosensory cortex (S1 and S2)
- S1 and S2 then innervate the Cc (cingulate cortex) and insula.


What do the somatosensory and cingulate cortexes perceive?

Somatosensory (S1 and S2): location, duration and intensity of pain.
Cingulate: emotional aspect of pain.


What endogenous inhibitory controls are in place for spinal descending pathways?

The PAG (periaqueductal grey of the midbrain) stimulated by the cortex/thalamus which in turn stimulates the NRM (nucleus raphe magnus of the medulla), which stimulates the release of opioid peptides/5HT/noradrenaline modulating glutamate release and thus pain, at the dorsal horn.


What occurs upon electrical stimulation of PAG/NRM?

Intense analgesia.


How do μ-opiod receptors modulate nociceptor signalling?

Located presynaptically, μ-opiod receptors increase opening of K+ channels (leading to hyperpolarisation thus difficulty firing), reduced Ca2+ channel opening (less Ca2+ = less glutamate release) and inhibition of adenylyl cyclase and reduction in cAMP.

This results in reduced neuronal excitability.


How do inhibitory interneurons act inside the dorsal horn?

- Release of GABA
- GABA A/B localised presynaptically (like μ-opiods) at nociceptor terminal
- Agonism of GABA receptors; Cl- gating, allowing Cl- in and thus resulting in hyperpolarisation, dampening excitation.