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The purpose of the study is to find subcutaneous equianalgesic doses of memantine, amantadine and bupivacaine and use these doses to quantify the cardiovascular and central nervous system toxicity of these agents after intravenous administration. Memantine, amantadine and bupivacaine, a local anesthetic, in a dose-related fashion were determined for cutaneous analgesia by a block of the cutaneous trunci muscle reflex in rats, and equipotent doses were calculated. Following rapid intravenous infusion of equianalgesic bupivacaine, memantine, amantadine and saline (vehicle) in rats, we observed the onset time of seizure, apnea and impending death, and monitored mean arterial blood pressure and heart rate. Memantine and amantadine elicited dose-dependent cutaneous analgesia. At the 50% effective dose (ED(50)), the rank of potencies was bupivacaine [1.8 (1.7-2.0)]>memantine [19.1 (17.6-21.8)]>amantadine [36.1 (32.0-40.3)] (P<0.05). On ED(25), ED(50) and ED(75) basis, the duration caused by bupivacaine was similar to that caused by memantine or amantadine. At equianalgesic doses, the infusion time of memantine or amantadine required to induce seizure, impending death, and apnea was longer than that of bupivacaine during rapid intravenous infusion (P<0.01). The decreasing slope in mean arterial blood pressure and heart rate was slower with memantine and amantadine when compared with bupivacaine at equivalent doses (P<0.01). Our data showed that memantine and amantadine (i) were equal to bupivacaine at producing durations of cutaneous analgesia but (ii) were less likely than bupivacaine to cause cardiovascular and central nervous system toxicity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Memantine blocks N-methyl-D-aspartate receptors and the Na(+) current, one principal mechanism of local anesthesia. Until now, no study mentioned that memantine had a local anesthetic effect, and therefore we investigated the local anesthetic effect of memantine., Methods: After blockade of cutaneous trunci muscle reflex with subcutaneous injections, we evaluated the cutaneous analgesic effect of memantine, lidocaine, and dizocilpine (MK-801) in rats. The dose-dependent response of memantine on cutaneous analgesia was compared with lidocaine and MK-801 in rats. The duration of action for each drug was evaluated and compared on an equipotent basis (20% effective dose [ED(20)], ED(50), and ED(80)). Lidocaine, a frequently used local anesthetic, was used as control., Results: We demonstrated that memantine, lidocaine, and MK-801 produced dose-dependent local anesthetic effects as infiltrative cutaneous analgesia. The relative potency was MK-801 (10.4 [9.7-11.1]) > memantine (17.6 [15.2-20.4]) > lidocaine (25.9 [23.8-28.1 ]) (P < 0.01). On an equipotent basis, memantine showed longer duration than lidocaine (P = 0.012) and MK-801 (P = 0.008). Coadministration of memantine (13.3 μmol/kg) and MK-801 (1.3 μmol/kg) produced greater blockade and duration than memantine (13.3 μmol/kg) or MK-801 (1.3 μmol/kg) alone. Neither local injection of saline nor intraperitoneal administration of a large dose of memantine, lidocaine, or MK-801 produced cutaneous analgesia (data not shown)., Conclusions: This study indicated that memantine is less potent than MK-801, and that memantine elicits longer analgesic duration than both lidocaine and MK-801. When combined with MK-801, memantine demonstrates a synergetic effect of cutaneous analgesia. We conclude that memantine produces better local analgesia than lidocaine and that N-methyl-D-aspartate receptors also contribute to the analgesic effect of memantine.

Although diphenhydramine has been shown to produce longer duration of spinal block than lidocaine, few studies disclose its skin infiltrative anesthesia when compared with a long-lasting local anesthetic, bupivacaine. The purpose of this study was to investigate whether diphenhydramine elicited cutaneous analgesia in comparison with bupivacaine. After inhibition of cutaneous trunci muscle reflex via subcutaneous injection of drugs in rats, we examined the local anesthetic effect of diphenhydramine and bupivacaine as infiltrative cutaneous analgesia in a dose-dependent fashion. We showed that diphenhydramine, as well as bupivacaine displayed a dose-dependent cutaneous analgesia in response to dorsal cutaneous noxious stimuli. The relative potency (50% effective dose) was bupivacaine (0.023 [0.013-0.035]%) > diphenhydramine (0.078 [0.068-0.091]%; P < 0.001). On an equipotent basis, diphenhydramine had a similar duration of action to bupivacaine. Neither local injection of saline nor intraperitoneal administration of a large dose of diphenhydramine or bupivacaine produced cutaneous analgesia (data not shown). We conclude that diphenhydramine is less potent than bupivacaine at producing cutaneous analgesia. At equipotent doses for infiltrative cutaneous analgesia, the duration of action of diphenhydramine is equal to that of bupivacaine. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to evaluate the local anesthetic effect of nisoxetine as infiltrative cutaneous analgesic. After rats were injected subcutaneously with nisoxetine, dose–response curves were constructed. The cutaneous anesthetic effect of nisoxetine or MK-801 (dizocilpine) was compared with lidocaine, a traditional local anesthetic. We found that nisoxetine and MK-801 acted like lidocaine and elicited dose-related cutaneous (local) anesthesia. The relative potency was nisoxetine>MK-801>lidocaine (P <0.01) as infiltrative anesthesia of skin. On an equianesthetic doses (20% effective dose [ED20], ED50, and ED80), nisoxetine produced longer action of cutaneous anesthesia than that of lidocaine or MK-801 (P <0.01). Coadministration of nisoxetine or lidocaine with MK-801 showed an additive cutaneous anesthesia. Neither local injection of a large dose of nisoxetine, MK-801 nor lidocaine in the thigh area produced cutaneous anesthesia (data not shown). In conclusion, nisoxetine had a local anesthetic effect as infiltrative cutaneous analgesia with durations of actions longer than that of lidocaine or MK-801. That N-methyl-d-aspartate receptors may not contribute to the cutaneous (local) anesthetic effect of nisoxetine or lidocaine. [Copyright &y& Elsevier]

Abstract: The aim of the study was to evaluate co-administration of clonidine with oxybuprocaine (ester type), bupivacaine (amide type) or dextrorphan (non-ester or non-amide type) and to see whether it could have a peripheral action in enhancing local anesthesia on infiltrative cutaneous analgesia in rats. Cutaneous analgesia was evaluated by a block of the cutaneous trunci muscle reflex (CTMR) in response to local dorsal cutaneous noxious pinprick in rats. The analgesic effect of the addition of clonidine with oxybuprocaine, bupivacaine or dextrorphan by subcutaneous injection was evaluated. On an ED50 basis, the rank of drug potency was oxybuprocaine>bupivacaine>dextrorphan (P <0.01). Mixtures of clonidine (0.12μmol) with oxybuprocaine, bupivacaine or dextrorphan (ED50 or ED95) extended the duration of action and increased the potency on infiltrative cutaneous analgesia. Among these drugs, the addition of clonidine to bupivacaine (amide type) elicits the most effective cutaneous analgesia. Clonidine at the dose of 0.12 and 0.24μmol did not produce cutaneous analgesia. Oxybuprocaine showed more potent cutaneous analgesia than bupivacaine or dextrorphan in rats. Co-administration of oxybuprocaine, bupivacaine or dextrorphan with clonidine increased the potency and duration on infiltrative cutaneous analgesia. The addition of clonidine to bupivacaine (amide type) elicits more effective cutaneous analgesia than oxybuprocaine (ester type) or dextrorphan (non-ester or non-amide type). [Copyright &y& Elsevier]

The aim of this study was to evaluate the effect of epinephrine as additive for propranolol as an infiltrative anesthetic. Using a rat model of cutaneous trunci muscle reflex (CTMR), we tested the effect of co-administration of epinephrine with propranolol on infiltrative cutaneous analgesia. Bupivacaine, a long-lasting local anesthetic, was used as control. Subcutaneous propranolol and bupivacaine elicited a dose-dependent local anesthetic effect on infiltrative cutaneous analgesia. On the 50% effective dose (ED 50 ) basis, the relative potency was bupivacaine [2.05 (1.95–2.21) μmol/kg]>propranolol [9.21 (9.08–9.42) μmol/kg] ( P <0.01 for each comparison). Subcutaneous epinephrine (0.012 μmol/kg) did not produce cutaneous analgesia. Mixtures of epinephrine (0.012 μmol/kg) with drugs (propranolol or bupivacaine) at ED 50 or ED 95 , respectively, intensified and prolonged drug action on infiltrative cutaneous analgesia. Intraperitoneal injection of combined drugs (propranolol or bupivacaine) at ED 95 with epinephrine (0.012 μmol/kg) exhibited no cutaneous analgesia. We concluded that propranolol was less potent but produced a similar duration of action when compared to bupivacaine on infiltrative cutaneous analgesia. Epinephrine as adjuvant for propranolol or bupivacaine enhanced the potency and extended the duration of action on infiltrative cutaneous analgesia. [ABSTRACT FROM AUTHOR]

Highlights: [•] Epinephrine produced more potent cutaneous analgesia than memantine or lidocaine. [•] Epinephrine increased the potency of memantine and lidocaine on cutaneous analgesia. [•] Epinephrine prolonged the duration of cutaneous analgesia of memantine and lidocaine. [Copyright &y& Elsevier]