Spinal supersensitivity to 5-HT₁, 5-HT₂ and 5-HT₃ receptor agonists following 5,7-dihydroxytryptamine

The present study examined functional supersensitivity to 5-hydroxytryptamine (5-HT) and 5-HT ligands selective for 5-HT₁, 5-HT₂ and 5-HT₃ receptors in two tests for nociception following the spinal administration of 5,7-dihydroxytryptamine (5,7-DHT). Intrathecal pretreatment with 5,7-DHT 30-100 μg (following desipramine) produced a selective depletion of spinal cord 5-HT levels of >80% and augmented the antinociceptive action of 5-HT in the tail flick and hot plate tests. The tail flick test was the more sensitive test for expression of this action. Supersensitivity was observed with the 5-HT₁ receptor ligands CGS 12066B (7-trifluoromethyl-4-(4-methyl-1-piperazinyl-pyrrolo[1,2-a]quinoxalinedimaleate), RU 24969 (5-methoxy-3-(1,2,4,6-tetrahydro-4-pyridinyl)1H indole succinate), TFMPP (m-trifluoromethylphenyl-piperazine HCl), mCPP (1-(3-chlorophenyl)piperazine dihydrochloride) and 5-Me-ODMT (5-methoxy-N,N-dimethyltryptamine hydrogen oxalate) but not with the 5-HT₂ receptor ligand DOI ((±)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane HCl) or the 5-HT₃ receptor ligand 2-Me-5-HT (2-methyl-5-hydroxytryptamine maleate) in the tail flick test. In the hot plate test, supersensitivity was observed only with 5-Me-ODMT. Intrathecal pretreatment with fluoxetine, a 5-HT uptake inhibitor, potentiated the action of 5-HT but not any of the other 5-HT₁ receptor ligands examined. These results indicate that supersensitivity occurs with 5-HT and 5-HT₁ receptor ligands but not with 5-HT₂ or 5-HT₃ receptor ligands. Both the loss of uptake sites and receptor upregulation may contribute to enhanced activity of 5-HT, but for other ligands, only the latter mechanism appears to occur.