NEUROPATHY: TOPSY-TURVY SPINAL TRANSMISSION? Dr Andrew Marshall - - PowerPoint PPT Presentation

PAIN IN DIABETIC NEUROPATHY: TOPSY-TURVY SPINAL TRANSMISSION?

Dr Andrew Marshall Anne Worthington

Painful Diabetic Neuropathy

• 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

“good” pain “phantom” pain? “bad” pain

HIGHER SENSORY PROCESSING Spontaneous thalamic activity Decreased cortical inhibition Loss of descending inhibition PERIPHERAL INFLAMMATION Local release of diverse pro- inflammatory factors NOCICEPTOR TRANSDUCTON Increased TRP receptors (A1, V1, V4) SPINAL PRESYNAPTIC ACTIVITY Increased Ca2+ channels (N-type, α2δ1) Increased TRP receptors (A1, V1, V4) AXONAL INSTABILITY Increased Ca2+ channels (T-type, α2δ1) Altered expression of NaV channels SPINAL POSTSYNAPTIC ACTIVTY Decreased KCC2 (loss of GABAA inhibitory function, gain of GABAA excitatory function) Increased excitatory receptor expression NMDA receptor activation SPINAL ENVIRONMENT Pro-inflammatory glial cells (microglia,

• ligodendrocytes)

Plausible Mechanisms of Painful Diabetic Neuropathy

Lee-Kubli and Calcutt. Handbook Clin. Neurol. 2014

Some inconvenient spinal truths………

Calcutt et al., 2000 Freshwater et al. 2002 Malmberg et al. 2006 Malisza et al. 2009 PNS electrical hyperactivity does not translate into increased spinal transmitter input

Spinal GABA

Diabetes

KCC2

Excitatory GABAA Tactile allodynia + formalin-evoked hyperalgesia

A Spinal Contribution to Painful Diabetic Neuropathy

Increased GABA release

BDN F ? ?

Anti-BDNF KCC2 activators GABAA inhibitors

Jolivalt et al. 2008 and Lee-Kubli and Calcutt, 2014b, with homage to Coull and DeKonick, 2003

H-Reflex Rate Dependent Depression (RDD): A Biomarker of Spinal Inhibitory Function?

Lee-Kubli et al. Curr. Diab. Rep. 2018

RDD measures spinal GABAergic inhibition

• RDD in normal animals is ablated by GABAA

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 GABAA

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

Testing RDD in humans

RDD highly conserved across mammals

RDD in Type 1 Diabetic Patients

Marshall et al. Diabetes 2017

RDD in Type 2 Diabetes

Worthington et al. SfN 2018

Human

RDD in Type 2 Diabetes

Worthington et al. SfN 2018

Human Rat

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

A Clinical Screening Paradigm for Neuropathic Pain

Patient #1: RDD normal Patient #2: RDD abnormal

• Spinal inhibition OK
• Spinal GABAA inhibitory
• Peripherally derived pain?
• Treat with agents that

reduce peripheral drive: pregabalin/NaV blockers etc

• Spinal disinhibition
• Spinal GABAA excitatory
• Spinally derived pain?
• Treat with spinal drugs that
• vercome disinhibition:

duloxetine/GABAA antagonist?

AIDED AND ABETTED BY………......

UCSD Nigel Calcutt Corinne Jolivalt Corinne Lee-Kubli Annika Malmberg University of Manchester Rayaz Malik

Normal Spinal Inhibition Spinal Disinhibition

Condition

Normal rats, taxol- CIPN Diabetic rats BDNF-treated rats DIOA-treated rats

Pain

Allodynia/hyperalge sia Allodynia/ hyperalgesia

Spinal KCC2

Normal Decreased

GABA function Effect of bicuculline

Impairs RDD/no pain alleviation Restores RDD/alleviates pain

Duloxetine

No effect in taxol Alleviates pain GABA GABAA receptors chloride influx INHIBITION GABA GABAA receptors chloride efflux EXCITATION

Lee-Kubli and Calcutt, 2014b

RDD

Normal Diminished/absent