# Presentation: 153673

## Genetic and environmental influences on the transition from acute to chronic pain

**Ze’ev Seltzer, DMD**
- Professor of Genetics
- Canada Senior Research Chair
- University of Toronto CTR for the Study of Pain

## 	 Pathophysiology of the transition from acute to chronic pain
 Comparative pain genetics
 Animal models
 Heritability and genetic assays
 Expected gains for pain medicine

-  Comparative pain genetics
-  Animal models
-  Heritability and genetic assays
-  Expected gains for pain medicine

- Presentation outline

## Brief update

Pathophysiology of the transition 
from acute to chronic pain

- Pathophysiology of the transition
- from acute to chronic pain

## What triggers the transition? - I

**L4**

**L5**

**L6**

**DRGs**

**Sciatic N**

**L3**

**Saphenous N**

**Totally **
**denervated**
**limb**

- Spinal
-  gate

- Brain

**Dorsal roots**

-  Electrical signal (“Injury discharge”; online/msec)

## Injury discharge

**3. Cut**

**Recording from a single neuron**

**Peripheral nerve**

**1.  Noxious & nonnoxious**
**      ****stimuli**

**2.  Electrical shock **
**     ****to determine **
**     ****fiber class: A****β****-****δ; C**

## Injury discharge

_**Prolonged “saw tooth” type**_
-  12% of cut afferents
- Lasts hours

**Sackstein et al (1999)**

## Injury discharge triggers neuropathic pain - I

**Efficacy of preemptive analgesia in humans is debated in the literature**

**Seltzer et al (1990a)**

## What triggers the transition? - II

**L4**

**L5**

**L6**

**DRGs**

**Sciatic N**

**L3**

**Saphenous N**

- Spinal
-  gate

**Dorsal roots**

-  Chemical signal(s) (Neurotrophic factors: e.g., NGF; hrs/days)

**Partially **
**denervated**
**limb**

## Neuroplastic changes following 
nerve injury

- nerve injury

**DRGs**

**Sciatic N**

**Saphenous N**

**Partially **
**denervated**
**limb**

_**PNS changes:**_** **
** ****Neuroma formation**

## Neuroplastic changes following 
nerve injury

**Partially **
**denervated**
**limb**

- Neuroplastic changes following
- nerve injury

**DRGs**

**Sciatic N**

_**PNS changes:**_** **
** ****Neuroma formation**
** ****Spontaneous firing **

**Production of novel**** **
**Na****+**** channels**
**Assembly in neuroma and DRG**

## Neuroplastic changes following 
nerve injury

- nerve injury

**DRGs**

**Sciatic N**

**Partially **
**denervated**
**limb**

_**PNS changes:**_** **
** ****Neuroma formation**
** ****Spontaneous firing **
** ****Firing induced by**
** ****chemical**** mediators (histamine,  bradykinin...)**
** ****M****echanical stimuli (e.g., malfitting prosthesis)**
** ****electrical stimuli (cross-talk, ephapses)**

## Neuroplastic changes following nerve injury (cont.)

**Partially **
**denervated**
**limb**

**DRGs**

**Sciatic N**

**Saphenous N**

**Sympathetic-Sensory link **
**Via NA & ****α****2-AR**

## Neuroplastic changes following nerve injury (cont.)

**Partially **
**denervated**
**limb**

**DRGs**

**Sciatic N**

**Saphenous N**

_**CNS changes:**_** **
** ****Loss of I****o**** & II****o**** ****/ microglia reaction / astroglia **
** ****Loss of receptors (e.g., opioid rec.) **
** ******** ****mediators + phenotypic switch (e.g., GABA depolarizes)**
** ****Rewiring of the pain network: **
**	******** ****tuning curves; novel modalities**
**	******** ****RFs**
**      ****segmental disinhibition**
**      ****central sensitization**
**      ****reduced efficacy of descending inhibition **

## Neuroplastic changes following nerve injury (cont.)

**Partially **
**denervated**
**limb**

**DRGs**

**Sciatic N**

**Saphenous N**

_**CNS changes:**_** **
** ****Loss of I****o**** & their terminals / microglia reaction / astroglia **
** ****Loss of receptors (e.g., opioid rec.) **
** ******** ****mediators + phenotypic switch (e.g., GABA depolarizes)**
** ****Rewiring of the pain network: **
**	******** ****tuning curves; novel modalities**
**	******** ****RFs**
**      ****segmental disinhibition**
**      ****central sensitization**
**      ****reduced efficacy of descending inhibition **

## Comparative approach:

Animal models used in pain genetics

- Animal models used in pain genetics

## Genetic selection based on spontaneous neuropathic pain

- Genetic selection based on _**spontaneous**_ neuropathic pain

**Neuropathic pain scores**

**Neuropathic pain scores**

## Neuropathic pain levels are strain specific / 2 species

- Var Pain  =  Var Gen +   Var Env

**Neuropathic pain scores**

**Seltzer et al (2001)**

**Seltzer & Shir (1998)**

**Mice     (****AXB-BXA Recombinant strains) **
**Parental strains**

## Stimulus-evoked chronic pain is also determined genetically

- _	__PSL model_
- Partial Sciatic tight Ligation

**L4**

**L5**

**L6**

**Dorsal roots**

**DRGs**

**Spinal nerves**

**Sciatic N**

**L3**

**Seltzer, Dubner, Shir (1990)**

**~1⁄2 sciatic thickness         trapped in a ligature**

**Partially **
**denervated**
**limb**

## Pain abnormalities in the PSL model - I 

**Shir & Seltzer (1998)**

**Allodynia**

## Pain abnormalities in the PSL model - II 

**Shir & Seltzer (1998)**

**Hyperalgesia**

## Acute pain - Tactile allodynia - Heat hyperalgesia - Spontaneous pain

**Spontaneous neuropathic pain (self-mutilation)**

**Shir et al (2001)**

**RATS (Mogil et al. in mice)**

## Conclusions

-  **Acute** pain sensitivity does not predict levels of **chronic **pain (3 different chronic pain models, 2 stimulus modalities, 2 species, 2 research groups).
- Levels of **spontaneous** chronic pain are not correlated with levels of **stimulus-evoked** chronic pain.
- If these results are translatable to humans, **genes are ‘syndrome-specific**’.  Pharmaco-genetic solutions will have to be tailored per syndrome.

## Heritability of chronic pain

How much of the variance is accountable by genetics?

- How much of the variance is accountable by genetics?

##  Nociception:  30-76% mean ~ 53%
Anti-nociception / analgesia:  23-68% mean ~ 45%
Neuropathic pain (SNL, Autotomy, PSL): ~ 30-70% mean ~50%

-  Nociception:  30-76% mean ~ 53%
- Anti-nociception / analgesia:  23-68% mean ~ 45%
- Neuropathic pain (SNL, Autotomy, PSL): ~ 30-70% mean ~50%

- Heritability in rodents

**Mogil et al (2002)**

## Heritability of pain in humans

- Pedigree analyses / twins studies: *h*2 ~ 0.2-0.7 (mean ~50%)
-   Sciatica
-   Diabetic neuropathy
-   Carpal tunnel syndrome
-  “Burning feet” syndrome
-   Post-herpetic neuralgia (HLA)
-   CRPS (HLA)
-   Fibromyalgia (HLA; *5HTTP1*)
-   Low back pain / Sciatica (*GCH1; BDNF*)
-   Migraine *(Cacna1a, ATP1A2, ...)*
-   TMD - Temporo-Mandibular Pain Disorder *(COMT)*
*  *Phantom limb pain / stump pain (HLA, *GCH1, GDNF*)
-   Post-Mastectomy Pain Syndrome *(COMT*, *GCH1)*

- Heritability of pain in humans

## Phenomics of chronic pain as a complex trait

## Different genes for different phenotypes

- Intensity

- Spatial

- Temporal

- Type

- Beliefs about pain

- Education

**Past painful**
**experiences**

**Impact **
**on QoL**

- Catastro-
- phizing

- Other

**Aggravating /**
**Relieving factors**

## Chronic pain phenomics

- _Choosing the right phenotypes for genetics: _
**Clinical relevance**
**Mechanism-based**
**N traits *****vs.***** multiple comparisons ****(“Bonferroni correction”) **
**Pooling / Indexing / Loosing resolution**
**Endophenotypes **

##      The Human Pain Phenome Project

 Detailed registry of previous chronic pain episodes
 Aetiology and medical history 
 Detailed phenotypes
 Tests (QST, electrodiagnosis, imaging, biochemistry)
 Treatment effects
 Additional traits: life style, personality / character
 Bioinformatics / data mining

** **Detailed registry of previous chronic pain episodes
-  Aetiology and medical history
-  Detailed phenotypes
-  Tests (QST, electrodiagnosis, imaging, biochemistry)
-  Treatment effects
-  Additional traits: life style, personality / character
-  Bioinformatics / data mining
** **

## Expected gains in pain genetics

##   - Diagnostic kits - Prognostic kits - Preventive pain medicine - Novel painkillers- New mechanisms- Gene therapy - Better animal models- Faster / cheaper clinical trials       

##   - Diagnostic kits - Prognostic kits - Preventive pain medicine - Novel painkillers- New mechanisms- Gene therapy - Better animal models- Faster / cheaper clinical trials       

##   - Diagnostic kits - Prognostic kits - Preventive pain medicine - Novel painkillers- New mechanisms- Gene therapy - Better animal models- Faster / cheaper clinical trials   

## United States Congress declared:
2001-2010: The Decade of Pain Control and Research

The Human Genome Project has developed methodological templates that can be transposed immediately to pain genetics.  

This is the time to:

 Establish new research teams

 Support the collections of DNA samples / multicenter approach

 Finance genome-wide screens using microarray chips  
  (1,000 samples X $ 500/ sample = $ 0.5 million / syndrome)   

               Proposed goal for 2010: First draft listing all major 		 		chronic pain genes in humans and mice.
		Given the right support – this is achievable !

- United States Congress declared:
- 2001-2010: The Decade of Pain Control and Research
- The Human Genome Project has developed methodological templates that can be transposed immediately to pain genetics.
- This is the time to:
-  Establish new research teams
-  Support the collections of DNA samples / multicenter approach
-  Finance genome-wide screens using microarray chips
-   (1,000 samples X $ 500/ sample = $ 0.5 million / syndrome)
-                _**Proposed goal for 2010:**_** **First draft listing all major 		 		chronic pain genes in humans and mice.
- 		Given the right support – this is achievable !

## Slide 35

## Injury discharge triggers neuropathic pain - II

**Seltzer et al (1990b)**

## Neuroplastic changes following nerve injury (cont.)

**DRGs**

**Sciatic N**

**Spontaneous firing in intact DRGs**

**Partially**
**denervated**
**limb**

**Saphenous N**

## Activity in neuroma and DRG causes pain

**Resection / RF / neurolysis of painful neuroma & GG -  **
**sometime successful **

**Devor et al (1999)**

## Different genes for different phenotypes

- Intensity

- Spatial

- Temporal

- Type

- Beliefs about pain

- Education

**Past painful**
**experiences**

**Impact **
**on QoL**

- Catastro-
- phizing

- Other

**Aggravating /**
**Relieving factors**

## Phenomics of chronic pain as a complex trait

## Chronic pain phenomics

- _Choosing the right phenotypes for genetics: _
**Clinical relevance**
**Mechanism-based**
**N traits *****vs.***** multiple comparisons ****(“Bonferroni correction”) **
**Pooling / Indexing / Loosing resolution**
**Endophenotypes **

##      The Human Pain Phenome Project

 Detailed registry of previous chronic pain episodes
 Aetiology and medical history 
 Detailed phenotypes
 Tests (QST, electrodiagnosis, imaging, biochemistry)
 Treatment effects
 Additional traits: life style, personality / character
 Bioinformatics / data mining

** **Detailed registry of previous chronic pain episodes
-  Aetiology and medical history
-  Detailed phenotypes
-  Tests (QST, electrodiagnosis, imaging, biochemistry)
-  Treatment effects
-  Additional traits: life style, personality / character
-  Bioinformatics / data mining
** **

## Acute pain - Tactile allodynia -  Heat hyperalgesia -  Spontaneous pain

**Spontaneous pain (self-mutilation)**

**Neuropathic pain score**

**%  Hyperalgesic mice**

**%  Allodynic mice**

**MICE**

## Thousands/~25K genes in the human genome encode the chronic pain network

**Sensory-discriminative  Affective                         Cognitive**

**“****Social” **
**pain genes**

**Nocifension / reflexive**

## No

_**No**_
-  **Most genes have been fixed throughout evolution **
**	****(e.g., *****“Painless” *****for noxious heat in the fly larva)**
** ****While many have Single Nucleotide Polymorphisms (SNPs)**
** ****Only a small fraction are functional, even fewer clinically relevant**
** ****So how many will have to treated to treat a given pain syndrome?**
**	****	****	****        **_**Not known as of yet**_
- 	**Guess: ~5 ‘major’ and up to ~15 ‘modifiers’ per syndrome**

- Shall we need to control thousands to treat pain ?

## How many genes would have to be 

- pharmaco-genetically controlled to
- provide solutions for a pain syndrome?

## Neuroplastic changes following nerve injury (cont.)

**A****δ****-fibers**

**DRGs**

**Sciatic N**

**Saphenous N**

**Collateral sprouting**

## Genetic and environmental influences on the transition from acute to chronic pain

**Ze’ev Seltzer, DMD**
- Professor of Genetics
- Canada Senior Research Chair
- University of Toronto CTR for the Study of Pain

## The case of Roni A. (male , age 44, contractor)

- L. brachial plexus avulsion
- L. hand numb and painful
- L. hand paralysed at an awkward position

##  1997 – surgical relocation of the arm

-  1997 – surgical relocation of the arm
-  2002 – amputation of the hand
- Telescoping
- Triggering the phantom from the face/arm
- Exacerbation of pain
- When symp system aroused
-  Changing weather
- When attempting to move phantom

## No therapy has helped Roni get rid of the pain