Peroxisome proliferator-activated receptor gamma (PPAR 3) is well-characterized as a key target of the thiazolinedione (TZD) class of anti-diabetic drugs. Our preliminary results describe the existence of PPAR 3 mRNA and protein in the dorsal horn. Furthermore, we demonstrate that the mechanical and thermal hypersensitivity associated with inflammation or nerve injury was rapidly reduced by intrathecal administration of rosiglitazone (a TZD) and 15d-PGJ2 (an endogenous PPAR 3 ligand) in a dose- and PPAR 3-dependent manner, and by systemic administration of pioglitazone, a BBB-permeant, FDA-approved ligand. The central hypothesis of this proposal is that ligand-dependent activation of PPAR3 in the dorsal horn decreases injury- induced activation of spinal neurons and glia that then dampens behavioral signs of inflammatory and neuropathic pain. The objective of the present application is to identify the mechanisms underlying PPAR- mediated inhibition of inflammatory or neuropathic pain, with a focus on pioglitazone. The long-term goal of our research program is to harness the therapeutic potential of PPAR signaling to alleviate chronic pain in humans.
AIM 1 will test the hypothesis that PPAR 3 agonists reduce allodynia and hyperalgesia. We will use pharmacological agents and nervous system-specific PPAR 3 deletion mutants to determine the contribution of PPAR 3 signaling in the spinal cord to the induction and maintenance of chronic pain. First, we will determine whether single intrathecal or systemic administration of pioglitazone and 15d-PGJ2 reduces behavioral signs of inflammatory and neuropathic pain. We predict that their analgesic actions will be blocked with PPAR 3 antagonists. Second, we will determine whether chronic intrathecal or oral administration of PPAR 3 agonists, begun before or after tissue or nerve injury, reduces behavioral signs of inflammatory and neuropathic pain. Third, we predict that anti-allodynic actions will not occur in mice with neuron-specific PPAR 3 knockdown.
AIM 2 will test the hypothesis that PPAR 3 ligands reduce injury-induced activation of neurons and microglia in the dorsal horn. Somatosensory stimulation of injured rats induces the expression of the immediate early gene, c-fos, in the superficial laminae of the dorsal horn. We predict that intrathecal pioglitazone will reduce inflammation- and nerve injury-induced expression of Fos immunoreactive neurons, as well as the expression of OX-42, a marker of microglia activation.
AIM 3 will test the hypothesis that endogenous PPAR 3 systems tonically inhibit allodynia. First, we will determine if PPAR3 expression occurs in neurons and/or glia that are activated during pain. Second, in an extension of Aims 1-2, we will determine whether receptor antagonists and genetic deletion increase allodynia and neuronal/glial activation. If affirmative, then we will determine whether the PPAR3 signaling elements co- vary with allodynia. At various times after nerve injury or persistent inflammation, we will evaluate: behavior and A) PPAR 3 mRNA and protein;B) phosphorylated PPAR 3;and C) 15d-PGJ2 levels with LC/MS/MS.
Chronic pain management is a major scientific and health care challenge, as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. We propose that ligands for peroxisome proliferator-activated receptor gamma (PPAR 3), such as rosiglitazone and pioglitazone, represent a novel class of analgesic / anti-allodynic compounds. These conceptually innovative experiments are important and timely because TZDs are commercially available for diabetes and are in clinical trials for CNS neurodegenerative diseases. Thus, confirmation of our hypothesis could lead to rapid translation to the clinical treatment of chronic pain.
|Griggs, Ryan B; Donahue, Renee R; Adkins, Braxton G et al. (2016) Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes. J Pain 17:359-73|
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|Taylor, Bradley K (2015) Resolvin D1: A New Path to Unleash the Analgesic Potential of Peroxisome Proliferator-activated Receptor-Î³ for Postoperative Pain in Patients with Diabetes. Anesthesiology 123:1231-2|
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|Maimaiti, Shaniya; DeMoll, Chris; Anderson, Katie L et al. (2015) Short-lived diabetes in the young-adult ZDF rat does not exacerbate neuronal Ca(2+) biomarkers of aging. Brain Res 1621:214-21|
|Griggs, Ryan B; Donahue, Renee R; Morgenweck, Jenny et al. (2015) Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARÎ³ mechanisms. Pain 156:469-82|
|Fu, Weisi; Taylor, Bradley K (2015) Activation of cannabinoid CB2 receptors reduces hyperalgesia in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Neurosci Lett 595:1-6|
|Griggs, Ryan B; Bardo, Michael T; Taylor, Bradley K (2015) Gabapentin alleviates affective pain after traumatic nerve injury. Neuroreport 26:522-7|
|Iannitti, T; Kerr, B J; Taylor, B K (2014) Mechanisms and pharmacology of neuropathic pain in multiple sclerosis. Curr Top Behav Neurosci 20:75-97|
|Taylor, Bradley K; Corder, Gregory (2014) Endogenous analgesia, dependence, and latent pain sensitization. Curr Top Behav Neurosci 20:283-325|
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