Effects of sufentanil on the release and metabolism of dopamine and ascorbic acid and glutamate release in the striatum of freely moving rats Pier Andrea Serra a , Giuseppe Susini b , Gaia Rocchitta a , Rossana Migheli a , Giuseppina Dessanti b , Egidio Miele a , Maria Speranza Desole a , Maddalena Miele a, * a Department of Pharmacology, University of Sassari, viale S.Pietro 43B, 07100 Sassari, Italy b Institute of Anesthesiology, University of Sassari, viale S.Pietro 43B, 07100 Sassari, Italy Received 22 January 2003; received in revised form 5 March 2003; accepted 21 March 2003 Abstract The effects of either intraperitoneally (i.p.) or intrastriatally administered sufentanil on the release and metabolism of dopamine (DA) in the rat striatum were evaluated using in vivo microdialysis. Dialysate concentrations of DA and its acidic metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased following i.p. administration of either clinical anesthetic (20 mg/kg) or clinical analgesic (1 mg/kg) sufentanil doses. In addition, sufentanil also increased uric acid concentrations. In contrast, dialysate ascorbic acid and glutamate concentrations were unaffected. Intrastriatal infusion of sufentanil (250 nM) induced only a short lasting decrease in dialysate DA. Subcutaneous naloxone (1.0 mg/kg) abolished sufentanil-induced increases in dialysate DA, DOPAC þ HVA and uric acid; however, naloxone (0.1 mM) failed to affect these increases when infused intrastriatally. These results demonstrate that sufentanil, at clinical doses, increases striatal DA release and oxidative metabolism of both DA and xanthine acting at extrastriatal sites with a m-receptor-mediated mechanism. q 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Sufentanil; Release; Metabolism; Dopamine; Ascorbic acid; Glutamate release; Striatum; Freely moving rats Sufentanil, a structural analog of fentanyl, is a potent analgesic of the 4-anilidopiperidine class of opioids which is commonly used either in the management of pain in patients undergoing surgery or, at higher doses, as an anesthetic in cardiac surgery [1,8]. There is strong evidence that morphine and morphine-like opioids influence the function of the central dopaminergic system. Acute morphine increases release [3,4,6] and oxidative metabolism [5,6] of dopamine (DA) in terminal fields of dopaminergic neurons. Besides the DA oxidative metabolism, morphine also causes increases in the hypoxanthine and xanthine oxidative metabolism [2,5], with a m-receptor-mediated mechanism [6]. Ascorbic acid is found in high concentrations throughout the mammalian brain. Neuronal ascorbic acid concen- trations (10 mM) are 20–25 times greater than those in the extracellular compartment (0.2–0.4 mM) [11,16]. A homeostatic mechanism regulates striatal extracellular ascorbic acid [11]. There is evidence from several different approaches that changes in neuronal activity are accompanied by changes in the extracellular concentration of ascorbic acid. Changes in extracellular ascorbic acid concentrations in the rat striatum in response to the systemic administration of non-volatile anesthetic agents have been proposed as an index of the level of neuronal activity [12]; in addition, ascorbic acid release into the extracellular fluid of the brain modulates both dopaminergic and glutamatergic transmissions [15]. It has been demonstrated that the release of ascorbic acid in the rat brain is dependent on impulse traffic, calcium influx, and glutamate uptake [10]. The ascorbic acid/glutamate heteroexchange [10], which is a physiological mechanism of the regulation of extracellular brain concentrations of both ascorbic acid and glutamate, is also considered one of the main mechanisms of neuropro- tection [16]. Recently, we demonstrated that ascorbic acid is the ultimate sink for radicals generated during metabolic activity of the nigro-striatal dopaminergic system [17]. In light of the above findings, the study of the effects of sufentanil on DA metabolism and ascorbic acid and 0304-3940/03/$ - see front matter q 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0304-3940(03)00395-1 Neuroscience Letters 344 (2003) 9–12 www.elsevier.com/locate/neulet * Corresponding author. E-mail address: pharmaco@ssmain.uniss.it (M. Miele).