Neuro-Genetics of Pain - National Institute on Drug Abuse

Neuro-Genetics of Pain - National Institute on Drug Abuse

Genetic and environmental influences on the transition from acute to chronic pain ZeevSeltzer, Seltzer,DMD DMD Zeev ProfessorofofGenetics Genetics Professor CanadaSenior SeniorResearch ResearchChair Chair Canada Universityof ofToronto TorontoCTR CTRfor forthe theStudy StudyofofPain Pain University

Presentation outline Pathophysiology of the transition from acute to chronic pain Comparative pain genetics Animal models Heritability and genetic assays Expected gains for pain medicine Brief update Pathophysiology of the transition from acute to chronic pain What triggers the transition? - I Electrical signal (Injury discharge; online/msec) Brain L3 Spinal gate DRGs L4

Saphenous N L5 L6 Dorsal roots Sciatic N Totally denervated limb Injury discharge Recording from a single neuron 2. Electrical shock to determine Peripheral nerve fiber class: A-; C 3. Cut

1. Noxious & nonnoxious stimuli Injury discharge 25% of cut A-fibers 50 0 400 30 0 20 0 10 0 0 Nerve cut 400 200

time (sec) 600 Time after cut (sec) 800 Firing frequency (Hz) Firing frequency (Hz) 33% of cut C-fibers Prolonged saw tooth type 120 Lasts hours 60 1000

0 Nerve cut Sackstein et al (1999) 12% of cut afferents Time after cut (min) Injury discharge triggers neuropathic pain - I Neuropathic pain score Preemptive analgesia Vhcl Local anesthetic Efficacy of preemptive analgesia in humans is debated in the literature Seltzer et al (1990a) What triggers the transition? - II

Chemical signal(s) (Neurotrophic factors: e.g., NGF; hrs/days) L3 Spinal gate DRGs L4 Saphenous N L5 L6 Dorsal roots NGF Sciatic N Partially denervated limb

Neuroplastic changes following nerve injury DRGs Saphenous N Sciatic N PNS changes: Neuroma formation Partially denervated limb Neuroplastic changes following nerve injury DRGs Sciatic N Production of novel Na+ channels Assembly in neuroma

and DRG PNS changes: Neuroma formation Spontaneous firing Partially denervated limb Neuroplastic changes following nerve injury DRGs Sciatic N Partially denervated limb PNS changes: Neuroma formation Spontaneous firing Firing induced by

chemical mediators (histamine, bradykinin) Mechanical stimuli (e.g., malfitting prosthesis) electrical stimuli (cross-talk, ephapses) Neuroplastic changes following nerve injury (cont.) DRGs Saphenous N Sciatic N Sympathetic-Sensory link Via NA & 2-AR Partially denervated limb Neuroplastic changes following nerve injury (cont.) DRGs Saphenous N Sciatic N

CNS changes: Loss of Io & IIo / 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 Partially denervated limb Neuroplastic changes following nerve injury (cont.) DRGs Saphenous N

Sciatic N CNS changes: Loss of Io & 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 Partially denervated limb Comparative approach: Animal models used in pain genetics 10

Wistar d70 Score Neuropathic pain score Genetic selection based on spontaneous neuropathic pain Sabra Lewis 8 6 High Pain - HA Low Pain - LA 4 2 0 ~hundreds Generation

Currently generation 53 Devor and Raber 1990, 2005 % 100 80 Unselected Sabra LA HA % 100 80 60 60 40 40

20 20 0 0 Ne 0-2 ur o pat 3-5 sco hic p 6-8 res ain 9-11 Ne 0-2 uro 3-5 pat 6-8 h sco ic p 9-11 res ain BC (F1xHA)

BC (F1xLA) F1(HAxLA) Autotomy score d 63 Neuropathic painonscores Neuropathic pain levels are strain specific / 2 species 10 Rats 8 Var Pain = Var Gen + Var Env 6 4 2 0 LEW LA

FSL SAB SD Seltzer & Shir (1998) GEPR FIS HA Mice (AXB-BXA Recombinant strains) Parental strains Seltzer et al (2001) Stimulus-evoked chronic pain is also determined genetically

PSL model Partial Sciatic tight Ligation DRGs L3 L4 Dorsal roots Spinal nerves Sciatic N L5 L6 ~ sciatic thickness trapped in a ligature Seltzer, Dubner, Shir (1990) Partially

denervated limb Pain abnormalities in the PSL model - I Withdrawal threshold (g) Withdrawal threshold (g) Tactile allodynia: 20 Intact Intact 16 Partial Sciatic PSL Ligation Baseline 12

8 Allodyni a Injured side Sham side 4 0 -24 -21 -18 -4 -1 1 7 14

21 28 35 42 Time Tim(days) e (days) Shir & Seltzer (1998) Pain abnormalities in the PSL model - II Response duration (sec) Response duration (sec) Heat hyperalgesia: 10 Intact

8 6 PSL Baseline PSL 4 Hyperalges ia 2 0 -24 -18 -4 -1

1 7 14 21 28 35 42 (days) Time Time (days) Shir & Seltzer (1998) 2.5 2 1.5 1 0.5

0 LA LEW SD HA FSL SAB Touch INTACT 20 16 12 8 4 0 GEPR HA

SAB SD FSL LA LEW Disorder A 10 8 R2 = 0.002 R2 = 0.09 6 R2 = 0.005 4 Aut X HH

2 Aut X TA HH X TA 0 Shir et al (2001) 0 2 4 6 8 Disorder B 10 12 PSL

20 15 10 5 0 SD SAB LA LEW GEPR Tactile allodynia 20 HA FSL PSL

16 12 8 4 0 HA FIS 12 Heat hyperalgesia 25 GEPR W ith d rawal th resh o ld (g ) W ithdrawal threshold (g) FIS R esp o nse d u ratio n (sec)

Noxious heat INTACT 3 A u to to m y sco re o n d 63 R esponse duration (sec) Acute pain - Tactile allodynia - Heat hyperalgesia - Spontaneous pain RATS (Mogil et al. in mice) GEPR FSL LA LEW SAB SD Autotomy

Spontaneous neuropathic pain (self-mutilation) 12 10 8 6 4 2 0 HA FIS GEPR SD SAB FSL LA

LEW Conclusions 1. Acute pain sensitivity does not predict levels of chronic pain (3 different chronic pain models, 2 stimulus modalities, 2 species, 2 research groups). 2. Levels of spontaneous chronic pain are not correlated with levels of stimulus-evoked chronic pain. 3. 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? Total Number of Writhes Heritability in rodents 70 Vehicle Acetaminophen 60 50

40 * 30 20 * * 10 * * S R III /2 D B A

C B A C 58 B A LB /c C 3H /H e C 57 B L/ 6 C 57 B L/

10 A K R A 12 9 0 Mogil et al (2002) Nociception: 30-76% mean ~ 53% Anti-nociception / analgesia: 23-68% mean ~ 45% Neuropathic pain (SNL, Autotomy, PSL): ~ 30-70% mean ~50% Heritability of pain in humans Pedigree analyses / twins studies: h2 ~ 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) Phenomics of chronic pain as a complex trait Different genes for different

phenotypes Spatial Intensity Sensory discriminative Past painful experiences Temporal Type Chronic pain Education Affective / motivational Cognitive Beliefs

about pain Impact on QoL Other Catastrophizing 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 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 Given the right support this is achievable ! chronic pain genes in humans and mice. Injury discharge triggers neuropathic pain - II

Neuropathic pain score Electrical tetanization C-fibers Wind-up (0.5Hz) C-fibers A-fibers (0.1Hz) CON Local anesthetic Postoperative time (days) Seltzer et al (1990b) Neuroplastic changes following nerve injury (cont.) Spontaneous firing in intact DRGs DRGs

Saphenous N Sciatic N Partially denervated limb Activity in neuroma and DRG causes pain Devor et al (1999) Resection / RF / neurolysis of painful neuroma & GG sometime successful Different genes for different phenotypes Spatial Intensity Sensory discriminative

Past painful experiences Temporal Type Chronic pain Education Affective / motivational Cognitive Beliefs about pain Impact on QoL Other

Catastrophizing 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 0

2 4 6 8 Disorder B 10 12 C 3 H /J HH X TA 0 0 C B A /J Aut X TA

S M /J 2 D B A /2 J Aut X HH ` 2 A /J 4 4 B A L B /C J R2 = 0.005 1 2 9 /J 6

6 R IIIS /J R2 = 0.002 R2 = 0.09 A K R /J 8 Spontaneous pain (self-mutilation) 8 C 5 8 /J Disorder A 10 10

C 5 7 B L /6 J 12 Neuropathic pain score day 35 S core % Allodynic mice % Hyperalgesic mice Acute pain - Tactile allodynia - Heat hyperalgesia - Spontaneous pain MICE Mogil et al (1999) Mogil et al (1999) Thousands/~25K genes in the human genome encode the chronic pain network Sensory-discriminative Affective Cognitive Social

pain genes Nocifension / reflexive Shall we need to control thousands to treat pain ? 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 How many genes would have to be pharmaco-genetically controlled to provide solutions for a pain syndrome? Neuroplastic changes following nerve injury (cont.) Collateral sprouting DRGs Saphenous N

Sciatic N A-fibers Genetic and environmental influences on the transition from acute to chronic pain ZeevSeltzer, Seltzer,DMD DMD Zeev ProfessorofofGenetics Genetics Professor CanadaSenior SeniorResearch ResearchChair Chair Canada Universityof ofToronto TorontoCTR CTRfor

forthe theStudy StudyofofPain Pain University The case of Roni A. (male , age 44, contractor) 1995 - suffered an accident at work L. brachial plexus avulsion L. hand numb and painful L. hand paralysed at an awkward position 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

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