neuropathy topsy turvy


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


  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

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