Senses: Touch and Pain

What are the types of receptors cells involved with tactile stimuli?

Keratinocyte

Meissner's corpuscle

Merkel's disc

Hair receptor

Ruffini endings

Pacinian corpuscle

What are the sensory neurons involved with tactile stimuli?

Afferent neuron

Interneuron

Efferent neuron

What is the sensory neuron for tactile mechanoreception? Describe the size, myelination, conductance velocity

A-beta

size - 6-12 uM

myelination - normal

conductance velocity - 33-75 m/s (medium)

What are the sensory neurons for nociception? Describe the size, myelination, conductance velocity

A-delta

size - 1-5 uM

myelination - thin

conductance velocity - 3-30 m/s

C-fiber

size - 0.2-1.5 uM

myelination - none

conductance velocity - 0.5-2.0 m/s

What type of channels do mechanoreceptors and nociceptors both have?

piezo channels

What type of mechanoreceptors have piezo channels?

surface mechanoreceptors such as keratinocytes, Meissner's corpuscle, and Merkel's disc

Piezo channels

mechanically-activated cation channels (Mechanical pressure on the plasma membrane opens the Piezos so cations can flow through)

Tactile pathway

1. Mechanoreceptors or proprioceptors on the afferent sensory neuron detect stimulus and generates AP (stimulus sensitive cation channel opens allowing Na+ to enter which leads to a receptor potential (aka graded depolarization). Local Na+ flow opens the VG-Na+ channels a little further down the afferent neuron and the influx of Na+ generates the AP which is carried by A-beta primary afferent fibers)

   • Merkel's disc and keratinocytes are different, as they are separate from sensory afferent neurons.

     1. Touch opens stimulus-selective channels in the receptor cell which causes cations to flow in, leading to depol

     2. Local cation influx results in opening of VG-Ca2+ channels and SNARE mediated neurotransmitter release (Norepinephrine in merkel's disc and ATP in keratinocytes)

     3. Norepinephrine or ATP binds to ligand gated receptors on the afferent neuron (B2 adrenergic receptors on merkel's and P2X receptors on keratinocytes) that permits Na+ influx

     4. Resulting depol opens V-G Na+ channels in the afferent

     5. Huge amounts of Na+ entry cause AP in afferent which propagates to the CNS

2. Axon of the first order neuron travels straight up the spinal cord on the same side of the body until it reaches the medulla oblongata. It passes the message to the second-order neuron, via a synapse where is releases Glu onto the second order neuron, which (second order neuron) crosses over and travels to the thalamus.

3. In the thalamus, the message is passed to the third order neuron which delivers the signal to the primary somatosensory cortex

First pain v. second pain

First pain → feel sharp pain and it is easily localized (involves A-delta fibers)

Second pain → more prolonged and almost burning unpleasant pain that is poorly localized (C-fibers); occurs later (after first-pain)

Why are first pain and second pain separate phases?

due to the differing conduction velocities of the A-delta and C-fibers

Noxious stimuli pathway

1. Nociceptor on first-order afferent neuron detects noxious stimuli

   1. Nociceptors have both piezo and TRP channels that allow Na+ and Ca2+ movement

   2. Na+ and Ca2+ influx causes receptor potential (GP), depol opens VG-Na+ channels to initiate AP, AP propagates to axon terminals, AP triggers opening of VG-Ca2+ channels, Ca2+ influx allows SNARE-mediated vesicular release of Glu

2. Afferent neurons send message along their axons and release Glu to second order neuron in the dorsal horn of the spinal cord (body)(soma in the DRG) or medulla oblongata (face) (soma in trigeminal ganglion) and the second order neuron crosses to the other side of the brain, projecting to the thalamus

3. Second order synapses onto third order which projects to the primary somatosensory cortex in the parietal lobe

TRP channels

receptors that respond/open to noxious cold or heat and allow Na+ or Ca2+ to enter. They are also activated by specific ligands

there are different specialized TRP channels for thermal reception

Why does menthol cause a cool feeling while chili peppers cause a hot feeling?

There are different specialized TRP channels for thermal reception.

Menthol gives a cool feeling because it binds and opens TRPM8 channels, while chili peppers give a hot feeling because they bind and open TRPV1 receptors.

Explain the role of neuropeptide release in nociceptors and their effect

they release substance P and calcitonin gene-related peptide (CGRP), which promotes inflammatory pain, vasodilation, and extravasation (leakage of blood, lymph or other fluid)

Effect of neuropeptide substance P in nociception

activates mast cells, causing them to degranulate and release histamine, which causes neurogenic inflammation that further activates nociceptors, causes extravasation which leads to swelling and inflammation

Effect of neuropeptide CGRP in nociception

CGRP causes vasodilation, leading to increased superficial skin blood flow and redness

Erythromelalgia and describe pain related mechanism

disorder caused by GOF mutation in SCN9A

mutation leads to increases in frequency of APs in nociceptive afferents (more neurotransmitter and neuropeptide release) so that they report more pain.

Congenital insensitivity to pain (CIP) and describe pain related mechanism

condition caused by LOF mutation in Prdm12

Prdm12 is a transcription factor encoded by this gene and plays key roles in development and survival of nociceptors (so they have few intact nociceptors).

Individuals with this condition are unable to perceive physical pain in any part of their body. It is often diagnosed early and children usually self-mutilate unknowingly.

Application and mechanism by which lidocaine reduces pain

drug that is applied locally to block the generation and propagation of nociceptor AP as it inhibits VG-Na+ channels that are necessary for APs

Pros and cons of lidocaine use

Pro: blocks pain

Con: short lasting

Application and mechanism by which Gabapentin reduces pain

Drug that can be taken for partial seizures and nerve pain and it inhibits VG-Ca2+ channels in the dorsal horn of the spinal cord and decreases Ca2+ mediated vesicle release of Glu

Pros and cons of Gabapentin use

Pro: reduces pain

Con: doesn’t completely stop pain

Application and mechanism by which opioids reduce pain

Drug that acts as an agonist at opioid receptors to reduce pain. Includes physiological opioids such as beta-endorphin and enkephalin and pharmacological opioids such as derivatives of opium poppy like opium

Mechanism:

opioid receptors are G-alpha-i GPCRs that act pre and post synaptically (receptors found in both)

Pre-synapse --> inhibits production of cAMP and inhibits VG-Ca2+ channels so no release of neurotransmitters

Post-synapse --> Opens VG-K+ channels in post-synaptic cell which causes hyperpolarization, making it more difficult to induce an AP and also inhibits production of cAMP in the postsynaptic cell

Pros and cons of opioid use

Pro: relieves pain; there are opioid receptor antagonists that can block overdoses :)

Con: Can cause dependence and decrease breathing rate which can lead to death (via overdose) so the use and dose is closely monitored