neuropathy topsy turvy
play

PAIN IN DIABETIC NEUROPATHY: TOPSY-TURVY SPINAL TRANSMISSION? Dr Andrew Marshall Anne Worthington Painful Diabetic Neuropathy good pain bad pain phantom pain? 20-35% of diabetic patients with neuropathy suffer pain

0 downloads 3 Views 799 KB Size Report
  1. PAIN IN DIABETIC NEUROPATHY: TOPSY-TURVY SPINAL TRANSMISSION? Dr Andrew Marshall Anne Worthington

  2. Painful Diabetic Neuropathy “good” pain “bad” pain “phantom” pain? • 20-35% of diabetic patients with neuropathy suffer pain • Pain may be occasional, persistent or touch-evoked (allodynia) • Described as “burning”, “aching” or “tingling” • Impairs movement, sleep and general QOL • Pain may resolve as neuropathy progresses

  3. Plausible Mechanisms of Painful Diabetic Neuropathy HIGHER SENSORY PROCESSING Spontaneous thalamic activity Decreased cortical inhibition Loss of descending inhibition PERIPHERAL INFLAMMATION SPINAL POSTSYNAPTIC ACTIVTY Local release of diverse pro- Decreased KCC2 (loss of GABA A inflammatory factors inhibitory function, gain of GABA A NOCICEPTOR TRANSDUCTON excitatory function) Increased TRP receptors (A1, V1, V4) Increased excitatory receptor expression NMDA receptor activation SPINAL PRESYNAPTIC ACTIVITY Increased Ca 2 + channels (N-type, α 2 δ 1) Increased TRP receptors (A1, V1, V4) AXONAL INSTABILITY SPINAL ENVIRONMENT Increased Ca 2 + channels (T-type, α 2 δ 1) Pro-inflammatory glial cells (microglia, Lee-Kubli and Calcutt. Altered expression of NaV channels oligodendrocytes) Handbook Clin. Neurol. 2014

  4. Some inconvenient spinal truths ……… Calcutt et al., 2000 Freshwater et al. 2002 Spinal GABA Malmberg et al. 2006 Malisza et al. 2009 PNS electrical hyperactivity does not translate into increased spinal transmitter input

  5. A Spinal Contribution to Painful Diabetic Neuropathy Diabetes ? ? BDN Increased GABA release F Anti-BDNF KCC2 Tactile allodynia + Excitatory formalin-evoked GABA A hyperalgesia KCC2 activators GABA A inhibitors Jolivalt et al. 2008 and Lee-Kubli and Calcutt, 2014b, with homage to Coull and DeKonick, 2003

  6. H-Reflex Rate Dependent Depression (RDD): A Biomarker of Spinal Inhibitory Function? Lee-Kubli et al. Curr. Diab. Rep. 2018

  7. RDD measures spinal GABAergic inhibition • RDD in normal animals is ablated by GABA A antagonists so serves as a marker of normal GABA inhibitory function (Jolivalt et al. 2008 ) • RDD is impaired after spinal cord injury and is associated with loss of inhibitory GABAergic interneurons (Marsala et al. 2009) • RDD is absent in normal rats where GABA A becomes excitatory via manipulation of KCC2 (KCC2 inhibitors, elevated BDNF) • RDD is diminished in rat and mouse models of type 1 and type 2 diabetes, but not of CIPN Jolivalt et al 2008, Lee-Kubli and Calcutt, 2014b, Marshall et al. 2017

  8. Testing RDD in humans RDD highly conserved across mammals

  9. RDD in Type 1 Diabetic Patients Marshall et al. Diabetes 2017

  10. RDD in Type 2 Diabetes Human Worthington et al. SfN 2018

  11. RDD in Type 2 Diabetes Human Rat Worthington et al. SfN 2018

  12. RDD as a Biomarker of Spinal Disinhibition • 40% of diabetic patients with pain have loss of RDD (>2xSD of controls) • Loss of RDD may correlate with pain severity RDD deficit may be used to segregate patients with spinally-mediated pain in order to refine clinical trial populations and allow personalized medicine Marshall et al. Diabetes 2017

  13. A Clinical Screening Paradigm for Neuropathic Pain Patient #2: RDD abnormal Patient #1: RDD normal • • Spinal inhibition OK Spinal disinhibition • • Spinal GABA A inhibitory Spinal GABA A excitatory • • Peripherally derived pain? Spinally derived pain? • • Treat with agents that Treat with spinal drugs that reduce peripheral drive: overcome disinhibition: pregabalin/NaV blockers duloxetine/GABA A etc antagonist?

  14. AIDED AND ABETTED BY………...... UCSD Nigel Calcutt Corinne Jolivalt Corinne Lee-Kubli Annika Malmberg University of Manchester Rayaz Malik

  15. Normal Spinal Spinal Inhibition Disinhibition Condition Normal rats, Diabetic rats taxol- CIPN BDNF-treated rats DIOA-treated rats Pain Allodynia/hyperalge Allodynia/ sia hyperalgesia Spinal KCC2 Normal Decreased GABA GABA GABA function GABA A receptors GABA A receptors chloride influx chloride efflux INHIBITION EXCITATION Effect of Impairs RDD/no Restores pain alleviation RDD/alleviates pain bicuculline No effect in taxol Alleviates pain Duloxetine Lee-Kubli and RDD Normal Diminished/absent Calcutt, 2014b

Recommend Documents


the topsy turvy world of social media
The Topsy-Turvy World of Social Media

The Topsy-Turvy World of Social Media Ten Paradoxes of Social Media A view

you are thinking symptoms of neuropathy
YOU ARE THINKING.. Symptoms of

Oregon February 2017 Missed Opportunities Topics Patients with neuropathy

peripheral neuropathy george pope presenta3on of
Peripheral Neuropathy George Pope

Peripheral Neuropathy George Pope Presenta3on of neuropathy and ae3ology

auditory neuropathy does ccmv play role
Auditory Neuropathy Does cCMV Play

Auditory Neuropathy Does cCMV Play Role? Dr Kerryn Saunders, MBBS FRACP, The

case presentations
Case Presentations 50 yo M with DM II,

5/8/2014 Case Presentations 50 yo M with DM II, peripheral neuropathy,

peripheral neuropathy in the diabetic foot including
PERIPHERAL NEUROPATHY IN THE DIABETIC

PERIPHERAL NEUROPATHY IN THE DIABETIC FOOT INCLUDING CHARCOT Presentation to

case 1
Case 1 71 y/o woman with HTN and

Case 1 71 y/o woman with HTN and asthma February 2015 Just another

the effects of american ginseng extracts on
The Effects of American Ginseng

The Effects of American Ginseng Extracts on Streptozocin Induced Diabetic

treating non painful chemotherapy induced
Treating Non-painful

Treating Non-painful Chemotherapy-induced Peripheral Neuropathy (CIPN): On

binding of autoantibodies
Binding of Autoantibodies in The

7.2.2020 Demonstrating Novel Binding of Autoantibodies in The Pathogenesis

pain allostasis and sensitization
Pain, Allostasis and Sensitization

Pain, Allostasis and Sensitization Brief overview of pain mechanisms Pain

randomized double blind placebo controlled trial of
Randomized, Double-Blind,

Randomized, Double-Blind, Placebo-Controlled Trial of Recombinant Human C1

communicating w with k key s stakeholders t to develop a
Communicating w with K Key S

Communicating w with K Key S Stakeholders t to Develop a a N National R

chemical respiratory allergy
Chemical Respiratory Allergy Clinical

Chemical Respiratory Allergy Clinical Information and How To Use It and Improve

uncompromised ambient air quality in resource efficient
Uncompromised ambient air quality in

Uncompromised ambient air quality in resource- efficient buildings Roberta

indoor allergens
Indoor Allergens in NYC Housing:

This presentation is for informational purposes only and is not

disclosures
Disclosures TRPV1 Mediates

12/14/2012 Disclosures TRPV1 Mediates Anxious/Depressive No disclosures

pediatric migraine
Pediatric Migraine JA C K GL A D ST

Pediatric Migraine JA C K GL A D ST EIN , M . D PR O FESSO R O F PED IA T

sphpm summer vacation scholarship program
SPHPM Summer Vacation Scholarship

SPHPM Summer Vacation Scholarship Program Laura Langdon Bachelor of Health

diagnosing and treating pain based on the underlying
Diagnosing and Treating Pain Based on

Diagnosing and Treating Pain Based on the Underlying Mechanism Daniel J.

21 year old future computer programmer may 2016
21 Year Old Future Computer Programmer

10/3/2017 Index Case I Shekar N Kurpad MD PhD, Sanford J Larson Professor

international society of neuroscience 2018 annual meeting
International Society of Neuroscience

International Society of Neuroscience 2018 Annual Meeting Grand Ballroom,