Activation of peroxisome proliferator-activated receptor γ in brain inhibits inflammatory pain, dorsal horn expression of Fos, and local edema

Abstract

Systemic administration of thiazolidinediones reduces peripheral inflammation in vivo, presumably by acting at peroxisome proliferator-activated receptor γ (PPARγ) in peripheral tissues. Based on a rapidly growing body of literature indicating the CNS as a functional target of PPARγ actions, we postulated that brain PPARγ modulates peripheral edema and the processing of inflammatory pain signals in the dorsal horn of the spinal cord. To test this in the plantar carrageenan model of inflammatory pain, we measured paw edema, heat hyperalgesia, and dorsal horn expression of the immediate-early gene c-fos after intracerebroventricular (ICV) administration of PPARγ ligands or vehicle. We found that ICV rosiglitazone (0.5-50 µg) or 15d-PGJ 2 (50-200 µg), but not vehicle, dose-dependently reduced paw thickness, paw volume and behavioral withdrawal responses to noxious heat. These anti-inflammatory and anti-hyperalgesia effects result from direct actions in the brain and not diffusion to other sites, because intraperitoneal and intrathecal administration of rosiglitazone (50 µg) and 15d-PGJ 2 (200 µg) had no effect. PPARγ agonists changed neither overt behavior nor motor coordination, indicating that non-specific behavioral effects do not contribute to PPAR ligand-induced anti-hyperalgesia. ICV administration of structurally dissimilar PPARγ antagonists (either GW9662 or BADGE) reversed the anti-inflammatory and anti-hyperalgesic actions of both rosiglitazone and 15d-PGJ 2 . To evaluate the effects of PPARγ agonists on a classic marker of noxious stimulus-evoked gene expression, we quantified Fos protein expression in the dorsal horn. The number of carrageenan-induced Fos-like immunoreactive profiles was less in rosiglitazone-treated rats as compared to vehicle controls. We conclude that pharmacological activation of PPARγ in the brain rapidly inhibits local edema and the spinal transmission of noxious inflammatory signals.

15d-PGJ2-loaded in nanocapsules enhance the antinociceptive properties into rat temporomandibular hypernociception

“…Pharmacological activation of PPAR-γ in the brain and spinal cord rapidly inhibits the spinal transmission of noxious inflammatory signals and local edema. These results suggest that PPAR-γ plays an important role in pain modulation in the central nervous system (Morgenweck et al, 2010) as well as in peripheral tissues and in peripheral endings of somatic afferents (Napimoga et al, 2008a;Pena-dos-Santos et al, 2009).…”

Biology and Therapeutic Applications of Peroxisome Proliferator- Activated Receptors

“…Interestingly, inflammatory hyperalgesia is reduced by the PPAR ligand 15d-PGJ 2 [115,343]. This effect is possibly mediated by tissue macrophages and involves endogenous opioid-signaling pathways [343].…”

“…Reduced lung inflammation and inflammatory signaling in cardiomyocytes [124,426] RSG Mitigated colitis, reduced pancreatitis and lung inflammation, diminished kidney diseases; neuroprotection; mitigated renal manifestation of systemic lupus erythematosus [266,267,297,315,316,339] Troglitazone Reduced colitis and autoimmune encephalomyelitis [357,427] Pioglitazone Mitigated colitis, arthritis and autoimmune encephalomyelitis; neuroprotection [297, 328 , 357, 428, 429] Ciglitazone Inhibited inflammatory cell activation; reduced neuroinflammation [174,277] 15dPGJ2 Inflammatory pain reduction [115,343] PPAR 15-keto-PG E2 Required for proper mucus production; may reduce mucus obstruction in cystic fibrosis [310] to reduced carbohydrate oxidation and a switch toward lipid utilization in muscle [24]. The main effect of PPAR / activation in muscle is therefore to increase lipid oxidation.…”

“…PPAR is expressed in the nervous system and appears to affect brain glucose utilization [38,115]. Neurons have been classically considered to be insulin-insensitive, although the translocation of GLUT-3 to the neuronal cell membrane is increased by insulin [116] and special glucosensor neurons have been identified in the hypothalamus [117].…”

“…This effect is possibly mediated by tissue macrophages and involves endogenous opioid-signaling pathways [343]. TZDs may play a similar role in the central nervous system [115], raising the interesting possibility that anti-inflammatory PPAR ligands could be used to combat inflammatory pain. These findings suggest future applications of PPAR activators in the management of chronic inflammatory conditions Table 3.…”