פיסיולוגיה מורחב 08-9 Somatosensory System and Pain פיסיולוגיה מורחב 08-9 Somatosensory System and Pain lecture 8: Phantom limb and other chronic pain Prof. Marshall Devor, Ph.D. Dept. of Cell & Animal Biology and Center for Research on Pain Institute of Life Sciences Hebrew University of Jerusalem 658-5085 marshlu@vms.huji.ac.il

descending control phantom prototypical “neuropathic pain” Mind-body problem: “phantom sensation the best possible proof of the existence of the eternal soul. If an arm can survive physical destruction, why not the whole person?” Admiral Lord Nelson (died Battle of Trafalgar, 1805)

stump pain phantom pain

telescoping key distinctions phantom - phantom pain stump pain, allodynia variable onset/ persistence individual variability movement, telescoping

Plasticity of body schema: reference of sensation from face and chest into the phantom Chronholm 1953

median n. section D3 amputation >

Map distortion enhanced in patients with PLP Flor, Birbaumer … does remapping enhance pain, or does pain enhance remapping ?

Nerve injury  somatotopic remapping (DH, DCN, thalamus & SS cortex) Devor & Wall 1981 delete follicle  neighboring barrels expand van der Loos

df: “neuropathic pain” is pain associated with injury or dysfunction of the nervous system “The paradox of neuropathic pain”: …nerve injury should dull sensation, not enhance it ! spontaneous pain pain on movement & deep palpation allodynia/hyperalgesia hyperpathia

* central sensitization Chung model hypothesis: (CNS amplification of evoked & spontaneous afferent impulse activity)

2003 European survey on chronic pain n >46,000 )telephone survey( 16 European countries (including Israel) Adults (18 years old or older) sponsored by Mundipharma Criterion for "Chronic pain" Pain for > 6 months duration Pain within the past month Pain at least several times a week Pain intensity >5/10 Breivik et. EJP ‘05

Overall European Prevalence(n=46,394) 19% report "chronic pain" Pain – there's a lot of it ! Overall European Prevalence(n=46,394) 19% report "chronic pain" (%) (%) (n=46,394) Breivik et. EJP ‘05

How often does it hurt? 67% of sufferers report experiencing chronic pain all the time Frequency – Israel– (n=322) כמה פעמים בשבוע כל יום כל הזמן Breivik et. EJP ‘05

Main types of chronic pain headache incl. migraine backache & sciatica arthritis (esp. OA) chronic abdominal pain diffuse musculoskeletal (fibromyalgia) neuropathies (shingles (PHN), diabetes, trauma… ~5% of total, but most refractory, costly) Breivik et. EJP ‘05

What is the origin of the nerve impulses that are felt as a phantom limb ?

“neuromatrix” R. Melzack dorsal root ganglion nerve end neuroma

Following axotomy ectopic burst firing develops at the nerve end neuroma Following axotomy ectopic burst firing develops at the nerve injury site…. Wall & Gutnick ‘74 Devor & Govrin- Lippmann ‘78

Nystrom & Hagbarth ‘81

DRG peripheral nerve Matsuda et al. 1981

Following axotomy, ectopic burst firing develops at the nerve injury site…. and in the DRG (Wall & Devor ‘83)

Ectopic hyperexcitability in 10 afferent neurons is important for neuropathic pain, but what causes the ectopia ?? Liu et al. 2000

“Phenotype” of sensory neurons is closely regulated to ensure appropriate excitability and stimulus selectivity NGF, BDNF, NT3, GDNF spike activity ?

Na+-ch immuno-labeling at chronic injured axon end Devor et. 1989 Neuropathy (axonopathy, demyelination) alters the phenotype (behavior) of sensory neurons: protein trafficking NGF, BDNF, NT3, GDNF spike activity ? neuroma

X Axonopathy (and demyelination ?) alters the phenotype of sensory neurons: gene expression Waxman et ‘94 Nav1.3 control NGF, BDNF, NT3, GDNF DRG soma spike activity ? Chung et ‘02 axotomy Na-ch upregulation X

NGF, BDNF, NT3, GDNF Boucher et al. 2000 spike activity ?

nerve/plexus block spinal block phantom “neuromatrix” DRG central sensitization phantom “neuromatrix” DRG spinal block emergent pain rare (<1/23) (PLP “always” gone Tessler & Kleiman ’94; Boas, Satav personal comm.) PLP eliminated in ca. 50% of patients (Birbaumer et.J.Neurosci’97) nerve/plexus block

פיסיולוגיה מורחב Somatosensory System and Pain lecture 8: Phantom limb and chronic pains Prof. Marshall Devor, Ph.D. Dept. of Cell & Animal Biology and Center for Research on Pain Institute of Life Sciences Hebrew University of Jerusalem 658-5085 marshlu@vms.huji.ac.il

how much neuroma ? how much DRG ? 25% 75% Liu et al. 2000