PPARγ activation blocks development and reduces established neuropathic pain in rats

NEUROPHARMACOLOGY

卷:70

Article

Morgenweck, J.^1,2  Griggs, R. B.¹  Donahue, R. R.¹  Zadina, J. E.^2,3,4,5  Taylor, B. K.^1,2 

[1] Univ Kentucky Res Fdn, Dept Physiol, Lexington, KY 40536 USA

[2] Tulane Univ, Hlth Sci Ctr, Neurosci Grad Program, New Orleans, LA 70112 USA

[3] SE Louisiana Vet Hlth Care Syst, New Orleans, LA 70161 USA

[4] Tulane Univ, Hlth Sci Ctr, Dept Med, New Orleans, LA 70112 USA

[5] Tulane Univ, Hlth Sci Ctr, Dept Pharmacol, New Orleans, LA 70112 USA

关键词: Allodynia;    Hyperalgesia;    Nerve injury;    Pioglitazone;    Extracellular signal-related kinase;    Microglia;    Astrocyte;   

DOI  :  10.1016/j.neuropharm.2013.01.020

来源: Elsevier

【 摘 要 】

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is emerging as a new pharmacotherapeutic target for chronic pain. When oral (3-30 mg/kg/day in chow for 7 wk) or twice-daily intraperitoneal (1-10 mg/kg/day for 2 wk) administration began before spared nerve injury (SNI), pioglitazone, a PPAR gamma agonist, dose-dependently prevented multiple behavioral signs of somatosensory hypersensitivity. The highest dose of intraperitoneal pioglitazone did not produce ataxia or reductions in transient mechanical and heat nociception, indicating that inhibitory effects on hypersensitivity were not secondary to adverse drug-induced behaviors or antinociception. Inhibitory effects on hypersensitivity persisted at least one week beyond cessation of pioglitazone administration, suggestive of long-lasting effects on gene expression. Blockade of PPAR gamma with GW9662, an irreversible and selective PPAR gamma antagonist dose-dependently reduced the inhibitory effect of pioglitazone on hypersensitivity, indicating a PPAR gamma-dependent action. Remarkably, a single preemptive injection of pioglitazone 15 min before SNI attenuated hypersensitivity for at least 2 weeks; this was enhanced with a second injection delivered 12 h after SNI. Pioglitazone injections beginning after SNI also reduced hypersensitivity, albeit to a lesser degree than preemptive treatment. Intraperitoneal pioglitazone significantly reduced the nerve injury-induced up-regulation of cd11b, GFAP, and p-p38 in the dorsal horn, indicating a mechanism of action involving spinal microglia and/or astrocyte activation. Oral pioglitazone significantly reduced touch stimulus-evoked phospho-extracellular signal-related kinase (p-ERK) in lamina I-II, indicating a mechanism of action involving inhibition of central sensitization. We conclude that pioglitazone reduces spinal glial and stimulus-evoked p-ERK activation and that PPAR gamma activation blocks the development of and reduces established neuropathic pain. (C) 2013 Elsevier Ltd. All rights reserved.

【 授权许可】

Free