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 micrograms (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.
Sawynok
J
J
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Reid
A
A
D015116:5,7-Dihydroxytryptamine / Q000008:administration & dosage / Q000633:toxicity*; D000662:Amphetamines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000698:Analgesia; D000700:Analgesics / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001665:Binding Sites; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007278:Injections, Spinal; D008297:Male; D010146:Pain / Q000188:drug therapy*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation
D000662:Amphetamines; D000700:Analgesics; D007211:Indoles; D010879:Piperazines; D011810:Quinoxalines; D017366:Serotonin Receptor Agonists; C052561:CGS 12066B; C018406:1-(3-trifluoromethylphenyl)piperazine; C025145:5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole; D015116:5,7-Dihydroxytryptamine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C015068:1-(3-chlorophenyl)piperazine