Abstract
Background: Neuropathic pain is a chronic incapacitating painful condition for which there is no effective treatment. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that play key roles in modulating immune and inflammatory responses. The antinociceptive properties of PPAR-γ activation on development of neuropathic pain are not fully known.
 Objective: To determine the role of PPAR-γ activation on the development of neuropathic pain following chronic constriction injury and to elucidate underlying mechanisms.
 Methodology: Neuropathy was induced by chronic constriction injury of sciatic nerve in rats. Cold allodynia and thermal hyperalgesia were assessed and the markers of inflammation and nitroso-oxidative stress were estimated.
 Results: Pre-emptive administration of pioglitazone, a PPAR-γ agonist (3, 10 or 30 mg/kg, i.p. 1 hr before surgery and continued once daily for 2 weeks) dose-dependently attenuated paw withdrawal latency to cold (allodynia) and thermal (hyperalgesia) stimuli. Pioglitazone significantly reduced elevated TBARS, protein carbonylation, nitrite levels and markedly restored depleted GSH, and reduction in activities of SOD and catalase in injured nerves. Further, pioglitazone markedly reduced plasma extravasation and levels of pro-inflammatory cytokines TNF-α and IL-1β following nerve injury. Moreover, pioglitazone did not alter the locomotor activity. Pretreatment with PPAR-γ antagonist BADGE (30 mg/kg, i.p.) blocked the beneficial effects of pioglitazone. Essentially, pioglitazone promoted the long-lasing recovery and also prevented the development of neuropathic pain even after treatment termination.
 Conclusion: Pioglitazone, a PPAR-γ agonist receptor-dependently abolished the development of traumatic neuropathic pain and exerted long-lasting antinociceptive effects through reducing nitroso-oxidative stress and inflammation. Our findings strongly suggest that pre-emptive activation of PPAR-γ prevented or at least delayed the development of nerve injury-induced pain hypersensitivity.
Highlights
Peripheral nerve injury often results in neuropathic pain including both hyperalgesia and allodynia
Pioglitazone, a peroxisome proliferator-activated receptors (PPARs)- agonist receptor-dependently abolished the development of traumatic neuropathic pain and exerted long-lasting antinociceptive effects through reducing nitroso-oxidative stress and inflammation
Our findings strongly suggest that pre-emptive activation of PPAR- prevented or at least delayed the development of nerve injury-induced pain hypersensitivity
Summary
Peripheral nerve injury often results in neuropathic pain including both hyperalgesia and allodynia. Neuroinflammation occurs after nerve injury and involves release of various chemical mediators including pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, nitric oxide (NO) and prostaglandins (PGs) which can originate locally or from cells that infiltrate the site of inflammation [2,3]. These cells initiate inflammatory and immune response in which firstly the mast cells are activated followed by sequential recruitment and activation of neutrophils and macrophages [3]. Cold allodynia and thermal hyperalgesia were assessed and the markers of inflammation and nitrosooxidative stress were estimated
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