The neuro-anatomical sites and molecular mechanism of action of gabapentin (GBP)-morphine interaction to prevent and reverse morphine side effects as well as enhancement of the analgesic effect of morphine is not known. Therefore, we examined the combined effects of GBP-Morphine on acute morphine induced c-Fos expression in rat striatum. The combined effect of GBP-Morphine was examined by means of c-Fos immunohistochemistry. A single intraperitoneal injection (i.p.) of morphine (10 mg/kg), saline (control), co-injection of GBP (150 mg/kg) with morphine (10 mg/kg) was administered under anaesthesia. Ninety minutes after drugs administration the deeply anesthetized rats were perfused transcardially with 4% paraformaldehyde. Serial 40 mum thick sections of brain were cut and processed by immunohistochemistry to locate and quantify the sites and number of neurons with c-Fos immunoreactivity. Detection of c-Fos protein was performed using the peroxidase-antiperoxidase (PAP) detection protocol. Our present study demonstrated that, administration of GBP (150 mg/kg, i.p.) in combination with morphine (10 mg/kg, i.p.) significantly (p < 0.01) attenuated the acute morphine (10 mg/kg, i.p.) induced c-Fos expression in the rat striatum. Present results showed that GBP-morphine combination action prevented the acute morphine induced c-Fos expression in rat striatum. Moreover, this study provides first evidence of neuro-anatomical site and that GBP neutralized the morphine induced activation of rat striatum.