LAUSR

&NA; 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 PPAR&ggr;‐mediated mechanism in such WSE effects, we verified the ability of the PPAR&ggr; 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 &mgr;‐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 PPAR&ggr; antagonist GW‐9662 (1 mg/kg; s.c.) in acute and chronic schedules of administration. Moreover, the effects of GW‐9662 (5 and 10 &mgr;M) applied alone and in combination with morphine (10 &mgr;M) 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 PPAR&ggr; 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 PPAR&ggr; 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 PPAR&ggr;‐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.