Background: The purposes of this study were to evaluate the co-administration of clonidine with memantine and to determine whether it has a peripheral action in intensifying cutaneous analgesia.Methods: Cutaneous analgesia was examined through inhibition of the cutaneous trunci muscle reflex in response to the local noxious pinprick in rats. Effect of the added subcutaneous clonidine to memantine on infiltrative cutaneous analgesia was assessed and compared with the local anesthetic lidocaine.Results: On the 50% effective dose (ED50) basis, the rank of drug potency was memantine [4.05 (3.95-4.18) mu mol] > lidocaine [5.81 (5.70-5.98) mu mol] (p < 0.01). Clonidine at a dose of 0.12 mu mol did not elicit cutaneous analgesia. Mixtures of clonidine (0.12 mu mol) with drug (memantine or lidocaine) at ED50 or ED95 prolonged the duration of action and enhanced the potency as infiltrative cutaneous analgesia. Clonidine enhanced the lidocaine cutaneous analgesia in which had a better effect than added to memantine.Conclusions: Our resulting data showed that memantine displayed more potent cutaneous analgesia than lidocaine. Co-administration of memantine or lidocaine with clonidine increased the potency and duration of the cutaneous analgesia. Clonidine intensified the effects of lidocaine promoting cutaneous analgesia than added to memantine. (C) 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.