Basic pain science Flashcards
What genetic abnormalities result in erythromyalgia?
overactivation of Nav1.7
What are 2 types of A delta fibers and what do they do?
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
What are the 2 types of C fibers, and what kind of pain do they transduce?
Peptidergic - Thermal pain (CGRP, Sub P)
-Expresses Trk A receptor
Non-peptidergic - Mechanical pain
-Expresses c-Ret, a neurotropin receptor
Name the receptors that transduce these properties: heat, cold, acid, & chemical irritants.
TRPV1 - heat
TRPV8 - cold
ASIC - acid
TRPA1 - chemical
Which laminae do the following nociceptors project to? A delta, Abeta, & C
A delta - Laminae I & V (deeper DH)
C fiber - Laminae I & II (Superficial DH)
A beta - Laminae III, IV, V
Which laminae are the WDR on?
Laminae V
What types of broad category category inputs go to Laminae V?
Innocuous (A beta fibers) Noxious - Somatic (A delta & C fibers) - Visceral *Get Viscero-somatic convergence & referral pain
What is significance of WDR’s in CeS?
Involved in wind up
What are the 2 ascending pathways for implicated and pain, and what are the general functions?
Spinothalamic - sensory discriminitive aspect of pain
Spinoreticular - poorly localized pain
What areas of the brain are implicated in the affective components of pain?
Amygdala (via Parabrachial region ie. dorsolateral pons)
ACC
Insula
What are the 2 areas implicated in descending modulation of pain?
PAG
RVM - Rostroventral Medulla
What happens in a Nav 1.7 channel a) Gain of function/Overactivation b) AbN inactivation c) Loss of function
a) Erythromelalgia (MutN SCN9A gene)
b) PEPD - Paroxysmal Extreme Pain Disorder
c) Inability to detect pain/noxious stimuli
What type of pain is Nav 1.8 channel implicated in?
Thermal & Mechanical sensitivity (Inflammatory pain)
Req’d for cold transmission
Highly expressed in C fibers
What is the relevance of Nav 1.9 channel?
Expression in non-peptidergic DRG, trigeminal & myenteric neurons
Known to play a role in DM Neuropathy
List 3 types of Calcium channels implicated in nociception/pain?
N, P/Q, T Types
What calcium channel is implicated in the familial hemiplegic migraine & what is the gene mutation?
P/Q Type Ca2+ channels
Genes:
- CACNA1A
- ATP1A2
- SCN1A
What Na+ and Ca2+ channels are implicated in diabetic neuropathy?
- Nav 1.9
* N & T type Calcium channel
What calcium channel subunit is upregulated in nerve injury and hence targeted by Gabapentin & Pregabalin?
Alpha 2 delta subunit of the calcium channel
What are the 3 basic mechanisms of Peripheral sensitization?
1) Ectopic D/C
2) Increased expression & altered currents of Na+ channels
3) Upregulation TRPV1 channel
4) Wallerian Degeneration
Name 3 target receptors of neurogenic inflammation in peripheral sensitization?
1) TRPV1
2) TRPA1 (enviro toxins)
3) ASIC
Name 5 excitatory NT’s (GASP CAA)
Glutamate, Aspartate, Sub P, CGRP, ATP, Adenosine*
Name 5 inhibitory NT’s (AGES N AGES)
Adenosine, GABA, Enkephalins, Serotonin, NE, Acetylcoline, Glycine, Endorphins, Somatostatin
What are the 3 mechanisms of CeS?
1) NMDA R Sensitization/hypersensitivity
2) Disinhibition of inhibitory interneurons
3) Microglia Activation
Mechanisms underlying secondary hyperalgesia?
Heterosynaptic facilitation - A Beta afferents (normally respond to LT, now engage in pain transmission)
What chemical mediators are released with activated microglia in CeS?
TNF apha, IL1-beta, IL-6, BDNF
What is the receptor that BDNF attaches to?
TrK B
Where is low dose Naltrexone felt to work?
At the Toll Like Receptors of the microglia
Which is the most predominant opioid receptor in the: a) peptidergic nociceptor b) Non-peptidergic nociceptor?
a) Peptidergic - Mu
b) Non-peptidergic - Delta
5 Features specific to CeS
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)
CeS is felt to play role in what 3 common pain disorders
FM, Migraine, IBS
Areas of the brain that play a role in CeS, name 5
ACC, Amygdala, Laminae I-V (SC), Spinal nucleus pars caudalis (Trigeminal nucleus), Thalamus
From fMRI & PET studies indicate CeS occurs in additional areas
- Parabrachial nucleus
- PAG
- Superior colliculus
- PFC
3 characterstics of noxious stimuli needed to induce CeS
Intense, Repeated, Sustained (IRS)
What are the 2 temporal phases of CeS?
1) Phosphorylation dependent phase
2) Transcription dependent phase
Name 6 chemical mediators play a role in activity dependent CeS?
Sub P, CGRP, Glutamate, BDNF, Bradykinin, NO
Compare & contrast Homosynpatic facilitation with heterotopic facilitation in how it manifests with CeS & PeS
Homosynaptic Changes (windup) - contribute with PeS to primary hyperalgesia Heterosynapatic Facilitation - alone, is responsible for secondary hyperalgesia + allodynia (CeS)
