Pain (me rn)

Question 1

Describe the structure and basic function of nociceptors

Answer 1

Arise from dorsal root ganglia

Unspecialised free nerve endings

A(delta), myelinated, 5 to 30 m/s OR C fibre unmyelinated axons <2 m/s (C fibres also do crude touch, temp, itch)

Discharge when strength of stimulus reaches high levels

Some are attached to thermoreceptors - activate at 43 degrees or below -17; also activated by capsaicin (from chili)

Question 2

What types of pain are there?

Answer 2

(pain at having 0 time to practice for an exam you know you could do well in but philosophy fucked you up the arse)

First pain - sharp, acute; A(delta)

Second pain - diffuse, long lasting; C fibre

Question 3

What are the types of A(delta) fibres?

Answer 3

Type 1 - mechano+chemical stimulation; high heat threshold

Type 2 - heat stimulation; high mechano-chemical threshold

Question 4

What do C fibres respond to?

Answer 4

Thermal + mechano + chemical = polymodal

But also heterogeneous - some responding to 2/3+ types etc

Question 5

Describe the properties of transient receptor potential channels and give some examples

Answer 5

VGK+ channels

6 transmembrane domains + pore = closed at rest; Na influx when active

Vanilloid receptor - TRPV1 - activated by capsaicin (from chili’s) + heat

TRPV4 - possible mechano-nociceptor

TRPA1 - chemical irritants including garlic and cigs (mmm)

Question 6

What other receptors are there for pain?

Answer 6

Piezo2 + ASIC receptors - possible mechanoreceptors

ASIC3 = skeletal + cardiac muscle pain from to pH changes secondary to ischemia

Question 7

What channel types are responsible for central pain transmission?

Answer 7

NaV1.7 - associated with pain disorders (mutations in the SCN9A gene that codes for the channel)

NAV1.7 - expressed in C fibre nociceptors

ONE OF THESE IS MEANT TO BE 1.8 NEEDS CHECKING

Question 8

What is the tract that carries pain information before decussation in the spinal cord called and what is its path?

Answer 8

Dorsolateral tract of Lissauer (fuck off)

Dorsal horn - up/down 1-2 spinal cord segments - penetrate grey matter of Rexed’s laminae I, II and V

Then become 2nd order neurons from I + V that ascend two spinal levels before decussating and ascending further to the brainstem/thalamus in the spinothalamic/anterolateral tracts

Question 9

Where do A(delta) and C fibres terminate?

Answer 9

A(delta) - I + V

C - exclusively in Rexed’s laminae I and II

Question 10

Where do A(beta) fibres terminate?

Answer 10

Non-nociceptive fibres

Rexed’s laminae III, IV, V

Some lamina V neurons have nociceptive and non = multimodal = wide-dynamic-range neurons = likely substrates for referred pain

Question 11

What information about the type of pain is the spinothalamic tract responsible for conveying?

Answer 11

Sensory-discriminative - Location, intensity, quality

From all modalities of pain

Relayed through fibres from the ventral posterior nucleus (VPL) to the somatosensory cortex

Question 12

How does the affective-motivational aspect of pain get conveyed?

Answer 12

Feeling of fear/anxiety; autonomic activation etc

Anterolateral system transmits to: reticular formation + periaquductal gray + superior colliculus + parabrachial nucleus (then to: hypothalamuus, amygdala, anterior cingulate cortex and insula) + medial thalamic nuclei (then to hypothalamus + anterior cingulate and insula)

Anterior cingulate = key in the ‘unpleasantness’ aspect of pain

Question 13

What is the pain matrix?

Answer 13

(what I’m living in rn, Jesus save me…)

The widespread involvement of neural structures involved in pain perception that explains the sensory, motor, affective and cognitive effects of pain

Question 14

How are noxious stimuli transmitted in the head and neck?

Answer 14

Trigeminal pathway

1st order neurons branches from CN V, VII, IX and X - medulla (in the spinal trigeminal tract) - spinal trigeminal nucleus (split into pars interpolaris + pars caudalis) - 2nd order neurons progress to various brainstem and thalamic targets such as the contralateral VPM and then on to the somatosensory cortex (for the sensory discriminative) + reticular formation etc (for the affective-motivational)

Question 15

What is the hypothesised general function of Rexed’s laminae I?

Answer 15

Responsible for interoception ie low level integration of information that represents the physiological condition of the body which when neurons ascend to higher levels, is responsible for the homeostatic control of functions (sweating etc)

Question 16

What is hyperalgesia?

Answer 16

Upon tissue damage, mildly noxious stimuli

elicit a significant pain response (to prevent further damage + attract healing/anti infection factors)

Question 17

What is peripheral sensitisation?

Answer 17

Nociceptor + inflammatory mediators release from active injury

Question 18

What are some examples of inflammatory mediators?

Answer 18

Neuronally mediated - substance P, calcitonin gene-related peptide (CGRP), ATP (all increase vasodilation and histamine release from mast cells)

Non-neuronal - mast cells, platelets, basophils, macrophages, neutrophils, endothelial cells, keratinocytes, fibroblasts - release H+, arachadonic acid, bradykinin, serotonin, prostaglandins, nerve growth factor, cyotkines (interlukin-1beta and TNF-alpha)

Most of these substances alter nociceptor fibre ion channels

(what a list wow)

Question 19

How do prostaglandins contribute to peripheral sensitisation?

Answer 19

Bind to GPCRs - increase cAMP in nociceptors

Decrease depolarisation threshold - phosphorylate TTX-resistant Na channels in nociceptors (like do i give a fuck)

Question 20

How do NSAIDs work? (should know this)

Answer 20

Irreversibly (only aspirin) inhibit COX1 - inhibit prostaglandin synthesis

MEDICINE BITCHES SUCK A DICK

Question 21

What is central sensitisation?

Answer 21

Due to increased excitation of dorsal horn neurons secondary to activation of nociceptor afferents, which are now able to generate action potentials in dorsal horn neurons = increased pain sensitivity

Thus these 2nd order neurons can also respond to normally innocuous stimuli and generate a central pain response (allodynia) - this can outlast the initial pain of the event by several hrs

Question 22

What is windup?

Answer 22

Progressive increase in the rate of discharge of dorsal horn neurons in response to repeated low frequency activation of nociceptive afferents

Arises from the summation of potentials evoked in dorsal horn neurons by nociceptive inputs and the sustained depolarisation of these neurons through opening of L-type Ca channels + removal of Mg2+ block from NMDA receptors - increasing sensitivity to Glu = the neurotransmitter used in nociceptive afferents

Question 23

What other mechanisms exist for central sensitisation?

Answer 23

NMDA receptor mediated elevations of CA2+ in post synaptic spinal cord neurons

Reduction in GABAergic and glycineric spinal cord inhibition, possibly secondary to K+Cl- cotransporter dysfunction

Role for astrocytes and microglia (especially in nerve injury/arthritis/chemo and cancer)

Question 24

What is the role of the periaqueductal gray?

Answer 24

Pain modulation - stimulation in rats produces behavioural analgesic effects and inhibits activity of nociceptive projection in the dorsal horn; also mediated by parabrachial nucleus, dorsal raphe, locus coeruleus and medullary reticular formation and the neurotransmitters 5HT, DA, ACh and histamine

Question 25

What is the Melzack-Wall gate theory of pain?

Answer 25

Pain is modulated by descending pain fibres as well as concomitant activation of the painful area with low threshold mechanoreceptors ie rub your head if you bump it, it will confuse your pain matrix and everything will be rosy

Question 26

What are endogenous opioids?

Answer 26

Enkephalins, endorphins, dynorphins

Responsible for pain modulation (in the areas mentioned as well as dorsal horn neurons) + their receptors is why we like to do skag init

Question 27

What are endocannabinoids?

Answer 27

Mans best friends.

(Also responsible for the selective suppression of nociceptive neurons via CB1 receptors in the dorsal horn of the spinal cord; centrally they decrease GABA and glutamate and modulate neuronal excitability; act on microglia by CB2 receptors)