Pioglitazone prevents morphine antinociceptive tolerance via ameliorating neuroinflammation in rat cerebral cortex

Abstract

Background: Opioid induced neuroinflammation is shown to be implicated in opioid analgesic tolerance development. In the present study the effect of pioglitazone on morphine-induced tolerance and neuroinflammation in the cerebral cortex of the rat was investigated. Materials and methods: Various groups of rats received morphine (10 mg/kg; ip) and vehicle (po), or morphine (10 mg/kg) and pioglitazone (20 or 40 mg/kg; po) once a day for 17 days. In order to determine the possible involvement of PPAR-gamma in the pioglitazone effect, one group of rats received PPAR-gamma antagonist, GW-9662 (2 mg/kg; sc), and pioglitazone (40 mg/kg) and morphine once daily for 17 days. Nociception was assessed using a tail flick apparatus and the percentage of the maximal possible effect was calculated as well. On 18th day, 2 h after the last morphine injection, the cerebral cortex of the animals were harvested and the tissue levels of tumour necrosis factor alpha, interleukin-1 beta, interleukin-6, interleukin-10 and nuclear factor-kappa B activity were determined. Results: Co-administration of pioglitazone (40 mg/kg) with morphine not only attenuated morphine-induced tolerance, but also prevented the up-regulation of pro-inflammatory cytokines (tumour necrosis factor alpha, interleukin-1beta, interleukin-6) and nuclear factor-kappa B activity in the rat cerebral cortex. Moreover, GW-9662 (2 mg/kg) administration 30 min before pioglitazone, antagonized the above mentioned pioglitazone-induced effects. Conclusion: It is concluded that oral administration of pioglitazone attenuates morphine-induced tolerance. This effect of pioglitazone may be, at least in part, due to its anti-inflammatory property which suppressed the cortical pro-inflammatory cytokine and inhibited of nuclear factor-kappa B activity. 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.