| Recent studies show synthetic PPARgamma thiazolidinediones (TZDs) rosiglitazone and pioglitazone, most notably implicated in treatment for type-2 diabetes, are useful to alleviate symptoms associated with neuropathic pain. To further characterize PPARgamma agonists as treatment for neuropathic pain we first evaluated the effects of repeated systemic administration of low doses of pioglitazone, with administration starting at the time of nerve injury, on the development of neuropathic pain. In an additional set of experiments, the beginning of drug administration was varied to determine if there is a therapeutic window. In both studies pioglitazone reduced the development of allodynia and hyperalgesia. These effects were a result of PPARgamma activation PPARgamma antagonist GW9662 significantly attenuated the therapeutic effects of pioglitazone. In established neuropathic pain, when administered at higher doses, we found that pioglitazone reversed nerve injury-induced allodynia and hyperalgesia. This was prevented with GW9662, indicating PPARa in its mechanism of action. To investigate site of action of pioglitazone, we administered the drug via direct intrathecal and intracerebroventricular (ICV) injection. Pioglitazone administered to the spinal cord produced anti-allodynic effects that were mediated via PPARgamma, while pioglitazone administered to the brain did not these results suggest a spinal rather than supraspinal site of action. Molecular markers for microglia, astrocytes, ERK and p38 were analyzed in rats receiving either repeated daily systemic administration or a single direct intrathecal injection of pioglitazone. Activated microglia, astrocytes, ERK and p38 were all significantly reduced in rats treated with systemic pioglitazone versus vehicle controls, whereas a single direct intrathecal injection of pioglitazone only reduced microglia activation. Together these results suggest treatment with pioglitazone inhibits the development and alleviates the maintenance of neuropathic pain. |
