# PPAR inhibition of spinal pain transmission

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $459,102

## Abstract

Diabetes affects 9% of the United States population and approximately one-third of these patients experience
chronic neuropathic pain, commonly referred to as painful diabetic neuropathy (PDN). PDN is difficult to
manage as analgesic treatments are only effective in a small subset of PDN patients. The development of
analgesics for pain associated with diabetes, in particular type 2 diabetes, is stalled by our incomplete
understanding of the underlying mechanisms of PDN. An important new clue comes from the recent finding
that methylglyoxal (MG), a highly reactive dicarbonyl product of glycolysis that accumulates with
hyperglycemia, is particularly high in patients with PDN. MG causes non-enzymatic glycation of proteins. The
resulting protein adducts, or advanced glycation end products (MG-AGEs), are toxic and contribute to diabetic
complications including PDN. Our central hypothesis is that elevated MG in type 2 diabetes causes pain and
that this can be alleviated with new classes of drugs targeting MG itself, TRPA1, AC1, Epac, and PPARγ. To
test the hypothesis that MG drives neuropathic pain (PDN) in type 2 diabetes, Specific Aim 1 will first
determine whether elevations in MG and its metabolizing enzyme, Glyoxalase-1, occur in pain processing
tissues in the hereditary Leprdb/db (db/db) mouse and Zucker Diabetic Fatty (ZDF) rat models of type 2
diabetes. We then ask whether a promising new class of MG-scavenging peptides will alleviate affective pain
and spinal pain transmission. Our preliminary data indicate that genetic deletion or pharmacological inhibition
of TRPA1, a glycation target of MG, blocks MG-induced pain. Indeed, TRPA1 is a leading target for the
development of new analgesics for chronic pain, but has not been tested in models of type 2 PDN. To fill this
gap, Specific Aim 2 will test the hypothesis that TRPA1 antagonists reduce affective pain and spinal pain
transmission in db/db mice and ZDF rats. Consequent to TRPA1 channel opening (e.g. by MG), the resulting
Ca2+ influx into the cell leads to the activation of Ca2+-sensitive proteins, which includes adenylyl cyclase I
(AC1). Our data indicate that selective inhibition of AC1 with NB001 blocks type 2 PDN. AC1 generates the
intracellular second messenger, cAMP, which targets not only protein kinase A but also exchange protein
directly activated by cAMP (Epac). Specific Aim 3 will use novel Epac1 and Epac2 small molecule inhibitors to
determine which of these targets drive PDN. Among the 33 original research articles, reviews, and a book
published during the previous funding cycle (22 with the PI as first or senior author), our Progress includes the
discovery that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist that is FDA-
approved to treat diabetes, acts at dorsal horn neurons to inhibit the chronic pain associated with cutaneous
inflammation and traumatic nerve injury. Our new data indicate additional efficacy in PDN and MG-induced
pain, with sur...

## Key facts

- **NIH application ID:** 9894861
- **Project number:** 5R01NS062306-11
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** BRADLEY K. TAYLOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $459,102
- **Award type:** 5
- **Project period:** 2008-12-18 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894861

## Citation

> US National Institutes of Health, RePORTER application 9894861, PPAR inhibition of spinal pain transmission (5R01NS062306-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9894861. Licensed CC0.

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