Modulation of formalin-induced behaviors and edema by local and systemic administration of dextromethorphan, memantine and ketamine

The present study examined the effects of local peripheral and systemic administration of three clinically used excitatory amino acid receptor antagonists (dextromethorphan, memantine, ketamine) on pain behaviors and edema produced by formalin (1.5% and 5%) in rats. Peripheral administration of dextromethorphan produced a locally mediated suppression of flinching behaviors induced by 1.5% and 5% formalin, but biting/licking behaviors were not affected. Memantine and ketamine had no effect on either of these behaviors. All three agents augmented edema produced by 1.5% and 5% formalin. When administered alone, dextromethorphan, memantine and ketamine produced an intrinsic paw swelling response, and this was blocked by the biogenic amine receptor antagonists mepyramine, phentolamine, methysergide and ketanserin. Following systemic administration, all three agents suppressed biting/licking behaviors, had no effect on flinching behaviors, and suppressed paw swelling induced by 5% formalin to varying degrees. These results provide evidence for a peripherally mediated antinociceptive action of dextromethorphan in the rat formalin test, but this may not necessarily be due to block of excitatory amino acid receptors as it is not observed with memantine or ketamine. All three agents produce a peripherally mediated paw swelling, which is likely due to blockade of biogenic amine reuptake. Systemic administration of all three agents produces antinociceptive and anti-inflammatory actions that may be due to block of excitatory amino acid receptors in the spinal cord.