Search

Graphical abstract Abstract Notwithstanding the experimental evidence indicating Withania somnifera Dunal roots extract (WSE) ability to prolong morphine-elicited analgesia, the mechanisms underlying this effect are largely unknown. With the aim of evaluating a PPARγ-mediated mechanism in such WSE effects, we verified the ability of the PPARγ antagonist GW-9662 to modulate WSE actions. Further, we evaluated the influence of GW-9662 upon WSE / morphine interaction in SH-SY5Y cells since we previously reported that WSE hampers the morphine-induced μ-opioid receptor (MOP) receptor down-regulation. Nociceptive thresholds / tolerance development were assessed in different groups of rats receiving vehicles (control), morphine (10 mg/kg; i.p.), WSE (100 mg/kg, i.p.) and PPARγ antagonist GW-9662 (1 mg/kg; s.c.) in acute and chronic schedules of administration. Moreover, the effects of GW-9662 (5 and 10 μM) applied alone and in combination with morphine (10 μM) and/or WSE (0.25 and 1.00 mg/mL) on the MOP gene expression were investigated in cell cultures. Data analysis revealed a functional effect of the PPARγ antagonist in attenuating the ability of WSE to prolong morphine analgesic effect and to reduce tolerance development after repeated administration. In addition, molecular experiments demonstrated that the blockade of PPARγ by GW-9662 promotes MOP mRNA down-regulation and counteracts the ability of 1.00 mg/mL of WSE to keep an adequate MOP receptor availability. In conclusion, our results support the involvement of a PPARγ-mediated mechanism in the WSE effects on morphine-mediated nociception and the likely usefulness of WSE in lengthening the analgesic efficacy of opioids in chronic therapy. [ABSTRACT FROM AUTHOR]

Background: Morphine-induced tolerance is associated with the spinal neuroinflammation. The aim of this study was to explore the effects of oral administration of the pioglitazone, the peroxisome proliferator activated receptor gamma (PPAR-γ) agonist, on the morphine-induced neuroinflammation in the lumbar region of the male Wistar rat spinal cord. Results: Co-administration of the pioglitazone with morphine not only attenuated morphine-induced tolerance, but also prevented the up-regulation of pro-inflammatory cytokines (tumor necrosis factor alpha, interleukin- 1beta, and interleukin 6) and nuclear factor-kappa B activity. Administration of the GW-9662 antagonized the above mentioned effects of the pioglitazone. Conclusions: It is concluded that oral administration of the pioglitazone attenuates morphine-induced tolerance and the neuroinflammation in the lumbar region of the rat spinal cord. This action of the pioglitazone may be, at least in part, due to an interaction with the spinal pro-inflammatory cytokine expression and the nuclear factor-kappa B activity. [ABSTRACT FROM AUTHOR]

Long-term exposure to opiates induces tolerance to the analgesic effect and dependence. The purpose of the present study is to investigate the effects of pioglitazone, a peroxisome proliferator-activated receptors gamma (PPAR-γ) agonist, on the morphine-induced tolerance and dependence. Groups of rats received morphine in combination with a vehicle or pioglitazone (5, 10, 20, and 40 mg/kg) daily. Thirty minutes before pioglitazone (40 mg/kg), GW-9662, a selective PPAR-γ antagonist, (2 mg/kg) was administrated in order to evaluate the possible role of the PPAR-γ. Nociception was assessed by a tail flick apparatus, and the percentage of the maximal possible effect was calculated as well. For 9 days, rats received additive doses of morphine to induce dependence. Naloxone was administrated 2 h after the morphine last dose, and withdrawal symptoms were recorded for 45 min. Morphine administration to rats over a duration of 17 days resulted in the development of tolerance, whereas pioglitazone (40 mg/kg) delayed the day of the established tolerance for 15 days. Administration of pioglitazone also prevented morphine-induced 50 % effective dose (ED) shift to the right in the dose-response curve and increased the global analgesic effect of morphine. In addition, pioglitazone decreased the total withdrawal score significantly, whereas GW-9662 significantly reversed the pioglitazone effects on the morphine tolerance and dependence. The prevention of the morphine-induced glia activation and the proinflammatory responses were the possible mechanisms for pioglitazone effect on delaying the morphine tolerance and attenuating the dependence. [ABSTRACT FROM AUTHOR]