The analgesic effects of pioglitazone in the bone cancer pain rats via regulating the PPARγ/PTEN/mTOR signaling pathway in the spinal dorsal horn

Abstract

Background and ObjectivesBone cancer pain (BCP) remains a difficult clinical problem. This study examined whether pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is effective for attenuating BCP, and investigated the interaction between activation of PPARγ and phosphatase and tensin homolog deleted from chromosome 10 (PTEN) / mammalian target of rapamycin (mTOR) signal in the spinal dorsal horn (SDH) of BCP rats. MethodsWe tested the effects of intrathecal (i.t.) injection of adenovirus-mediated PTEN (Ad-PTEN), PTEN antisense oligonucleotide (Ad-antisense PTEN), mTOR inhibitor rapamycin, pioglitazone and PPARγ antagonist GW9662 on bone cancer-induced mechanical allodynia by measuring the paw withdrawal threshold (PWT). Western blot or immunofluorescence examined the expression of spinal PPARγ, PTEN, mTOR, p-mTOR and p-S6K1. ResultsBone cancer did not alter total mTOR expression but caused significant downregulation of PTEN and upregulation of p-mTOR and p-S6K1 in spinal neurons. Rapamycin markedly reduced BCP. Upregulation of spinal PTEN by i.t. Ad-PTEN significantly relieved BCP and downregulated p-mTOR and p-S6K1; while i.t. Ad-antisense PTEN led to the opposite effects of Ad-PTEN. Spinal PPARγ expression increased in BCP rats, co-localizing mainly with neurons and a few astrocytes, but not in microglia. Pioglitazone (500 μg/day i.t. for one week, from 7 days after surgery) attenuated BCP, further increased expression of PPARγ, and inhibited downregulation of PTEN and upregulation of p-mTOR and p-S6K1 in the SDH. Pioglitazone’s analgesic effect was enhanced by Ad-PTEN and attenuated by Ad-antisense PTEN. Blockade of PPARγ with GW9662 (300 μg i.t. 15 min prior to pioglitazone) reversed the effects of pioglitazone on BCP and regulations of PPARγ/PTEN/mTOR signal. ConclusionsIntrathecal pioglitazone administration alleviates BCP by regulating the PPARγ/PTEN/mTOR signal in the SDH. Our data provided new insight in the therapeutic strategy in BCP management.