dizocilpine-maleate and nisoxetine

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.

Topics: Anesthetics, Local; Animals; Diffusion; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fluoxetine; Injections, Subcutaneous; Kinetics; Male; Neurotransmitter Uptake Inhibitors; Nociceptive Pain; Norepinephrine; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reflex; Skin

1. The mechanism of stimulation of noradrenaline (NA) release by nicotine (NIC) was investigated in human cerebral cortex slices preloaded with 3H-noradrenaline. 2 NIC (10-1000 micro M) increased 3H-NA release in a concentration-dependent manner. 3. NIC (100 micro M)-evoked 3H-NA release was largely dependent on external Ca2+, and was attenuated by omega-conotoxin GVIA (0.1 micro M) but not by nitrendipine (1 micro M). 4. Tetrodotoxin (1 micro M) and nisoxetine (0.1 micro M) attenuated the NIC (100 micro M)-evoked release of 3H-NA. 5. Mecamylamine (10 micro M), dihydro-beta-erythroidine (10 micro M) and d-tubocurarine (30 micro M), but not alpha-bungarotoxin (alpha-BTX, 0.1 micro M), attenuated the NIC (100 micro M)-evoked release of 3H-NA. 6. NIC (100 micro M)-evoked release of 3H-NA was not affected by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 30 micro M) and D(-)-2-amino-5-phosphonopentanoic acid (D-AP5, 100 micro M), but attenuated by MK-801 (10 micro M). MK-801 (0.1-1000 micro M) displaced the specific binding of 3H-nisoxetine with K(i) values of 91.2 micro M. NIC (100, 300 and 1000 micro M) did not induce 3H-D-aspartate release in human cerebral cortex slices. 7. NIC (100 micro M)-evoked release of 3H-NA was attenuated by 7-nitroindazole (10 micro M), N(G)-nitro-L-arginine methyl ester HCl (L-NAME, 30 micro M), N(G)-monomethyl-L-arginine acetate (L-NMMA, 300 micro M). [(3)H]-NA release induced by NIC (100 micro M) was attenuated by methylene blue (3 micro M) and 1H-[1,2,4]oxadiazole[4,3-alpha]quinoxalin-1-one (ODQ, 10 micro M), and enhanced by zaprinast (30 micro M). 8. In conclusion, NIC stimulates the release of 3H-NA through activation of alpha-BTX-insensitive nicotinic acetylcholine receptors in the human cerebral cortex slices and this action of NIC is associated with modulation of the NO/cGMP pathway.

Topics: Adolescent; Adult; Arginine; Calcium; Calcium Channel Blockers; Cerebral Cortex; Dihydro-beta-Erythroidine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fluoxetine; Ganglionic Stimulants; Guanylate Cyclase; Humans; In Vitro Techniques; Indazoles; Male; Mecamylamine; Methylene Blue; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Nicotine; Nicotinic Antagonists; Nitrendipine; Nitric Oxide Synthase; Norepinephrine; omega-Conotoxin GVIA; Oxadiazoles; Purinones; Quinoxalines; Tetrodotoxin; Tritium; Tubocurarine