Basic pain science

Question 1

What genetic abnormalities result in erythromyalgia?

Answer 1

overactivation of Nav1.7

Question 2

What are 2 types of A delta fibers and what do they do?

Answer 2

Type I - HTM - Responds to mechanical/chemical stimuli, relatively high heat threshold >50 deg C

Type II - HTT - Responds to thermal stimuli, v. high mechanical threshold

Question 3

What are the 2 types of C fibers, and what kind of pain do they transduce?

Answer 3

Peptidergic - Thermal pain (CGRP, Sub P)
-Expresses Trk A receptor

Non-peptidergic - Mechanical pain
-Expresses c-Ret, a neurotropin receptor

Question 4

Name the receptors that transduce these properties: heat, cold, acid, & chemical irritants.

Answer 4

TRPV1 - heat
TRPV8 - cold
ASIC - acid
TRPA1 - chemical

Question 5

Which laminae do the following nociceptors project to? A delta, Abeta, & C

Answer 5

A delta - Laminae I & V (deeper DH)
C fiber - Laminae I & II (Superficial DH)
A beta - Laminae III, IV, V

Question 6

Which laminae are the WDR on?

Answer 6

Laminae V

Question 7

What types of broad category category inputs go to Laminae V?

Answer 7

Innocuous (A beta fibers)
Noxious
- Somatic (A delta & C fibers)
- Visceral 
*Get Viscero-somatic convergence & referral pain

Question 8

What is significance of WDR’s in CeS?

Answer 8

Involved in wind up

Question 9

What are the 2 ascending pathways for implicated and pain, and what are the general functions?

Answer 9

Spinothalamic - sensory discriminitive aspect of pain

Spinoreticular - poorly localized pain

Question 10

What areas of the brain are implicated in the affective components of pain?

Answer 10

Amygdala (via Parabrachial region ie. dorsolateral pons)
ACC
Insula

Question 11

What are the 2 areas implicated in descending modulation of pain?

Answer 11

PAG

RVM - Rostroventral Medulla

Question 12

What happens in a Nav 1.7 channel a) Gain of function/Overactivation b) AbN inactivation c) Loss of function

Answer 12

a) Erythromelalgia (MutN SCN9A gene)
b) PEPD - Paroxysmal Extreme Pain Disorder
c) Inability to detect pain/noxious stimuli

Question 13

What type of pain is Nav 1.8 channel implicated in?

Answer 13

Thermal & Mechanical sensitivity (Inflammatory pain)
Req’d for cold transmission
Highly expressed in C fibers

Question 14

What is the relevance of Nav 1.9 channel?

Answer 14

Expression in non-peptidergic DRG, trigeminal & myenteric neurons
Known to play a role in DM Neuropathy

Question 15

List 3 types of Calcium channels implicated in nociception/pain?

Answer 15

N, P/Q, T Types

Question 16

What calcium channel is implicated in the familial hemiplegic migraine & what is the gene mutation?

Answer 16

P/Q Type Ca2+ channels

Genes:

• CACNA1A
• ATP1A2
• SCN1A

Question 17

What Na+ and Ca2+ channels are implicated in diabetic neuropathy?

Answer 17

• Nav 1.9

* N & T type Calcium channel

Question 18

What calcium channel subunit is upregulated in nerve injury and hence targeted by Gabapentin & Pregabalin?

Answer 18

Alpha 2 delta subunit of the calcium channel

Question 19

What are the 3 basic mechanisms of Peripheral sensitization?

Answer 19

1) Ectopic D/C
2) Increased expression & altered currents of Na+ channels
3) Upregulation TRPV1 channel
4) Wallerian Degeneration

Question 20

Name 3 target receptors of neurogenic inflammation in peripheral sensitization?

Answer 20

1) TRPV1
2) TRPA1 (enviro toxins)
3) ASIC

Question 21

Name 5 excitatory NT’s (GASP CAA)

Answer 21

Glutamate, Aspartate, Sub P, CGRP, ATP, Adenosine*

Question 22

Name 5 inhibitory NT’s (AGES N AGES)

Answer 22

Adenosine, GABA, Enkephalins, Serotonin, NE, Acetylcoline, Glycine, Endorphins, Somatostatin

Question 23

What are the 3 mechanisms of CeS?

Answer 23

1) NMDA R Sensitization/hypersensitivity
2) Disinhibition of inhibitory interneurons
3) Microglia Activation

Question 24

Mechanisms underlying secondary hyperalgesia?

Answer 24

Heterosynaptic facilitation - A Beta afferents (normally respond to LT, now engage in pain transmission)

Question 25

What chemical mediators are released with activated microglia in CeS?

Answer 25

TNF apha, IL1-beta, IL-6, BDNF

Question 26

What is the receptor that BDNF attaches to?

Answer 26

TrK B

Question 27

Where is low dose Naltrexone felt to work?

Answer 27

At the Toll Like Receptors of the microglia

Question 28

Which is the most predominant opioid receptor in the: a) peptidergic nociceptor b) Non-peptidergic nociceptor?

Answer 28

a) Peptidergic - Mu

b) Non-peptidergic - Delta

Question 29

5 Features specific to CeS

Answer 29

1) Conversion nociceptive specific neurons to wide dynamic neurons (WDRs)
2) Temporal Wind-up - Increased response to innocuous stimulation vs PeS (Increased response/decreased threshold to noxious stimuli)
3) Expansion of spacial fields/Secondary Hyperalgesia vs PeS (restricted to site of injury)
4) Persistent changes despite lack of noxious input vs PeS (Req’s ongoing peripheral pathology)

5) Altered heat AND mechanical sensitivity (PeS - only heat)

Question 30

CeS is felt to play role in what 3 common pain disorders

Answer 30

FM, Migraine, IBS

Question 31

Areas of the brain that play a role in CeS, name 5

Answer 31

ACC, Amygdala, Laminae I-V (SC), Spinal nucleus pars caudalis (Trigeminal nucleus), Thalamus

Question 32

From fMRI & PET studies indicate CeS occurs in additional areas

Answer 32

• Parabrachial nucleus
• PAG
• Superior colliculus
• PFC

Question 33

3 characterstics of noxious stimuli needed to induce CeS

Answer 33

Intense, Repeated, Sustained (IRS)

Question 34

What are the 2 temporal phases of CeS?

Answer 34

1) Phosphorylation dependent phase

2) Transcription dependent phase

Question 35

Name 6 chemical mediators play a role in activity dependent CeS?

Answer 35

Sub P, CGRP, Glutamate, BDNF, Bradykinin, NO

Question 36

Compare & contrast Homosynpatic facilitation with heterotopic facilitation in how it manifests with CeS & PeS

Answer 36

Homosynaptic Changes (windup) - contribute with PeS to primary hyperalgesia
Heterosynapatic Facilitation - alone, is responsible for secondary hyperalgesia + allodynia (CeS)