5-hydroxytryptamine3 (5-HT3) receptors mediate spinal 5-HT antinociception: an antisense approach.
To examine the role of the 5-hydroxytryptamine(1B) (5-HT1B) and 5-HT3 receptor subtypes in the analgesia produced by 5-HT (serotonin) agonists, we assessed the effect of antisense oligodeoxynucleotides (AODNs) designed to "knock down" the number of these receptor subtypes on analgesia produced by intrathecal (i.t.) 5-HT, the 5-HT1B receptor agonist, 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline maleate (CGS-12066A), and the 5-HT3 receptor agonist, 2-methyl-5-HT. Groups of mice (n = 17-20) were injected i.t. on days 1, 3, and 5 with one of the AODNs, a mismatch oligo, or saline. On day 6, all mice were injected i.t. with 70.5 nmol of 5-HT, 44.4 nmol of CGS-12066A, or 49 nmol of 2-methyl-5-HT by lumbar puncture. Following testing, spinal cords were rapidly removed and prepared for receptor binding assays. Treatment with AODN for 5-HT1B receptors produced a 70% reduction in ligand binding to this receptor subtype. After treatment with AODN for 5-HT3 receptors, ligand binding to this receptor subtype was undetectable. In mice tested with i.t. 5-HT, tail-flick analgesia was attenuated only in mice treated with the 5-HT3 receptor AODN. Mice treated with the AODN designed to knock down 5-HT(1B) receptors or with its mismatch oligo were not significantly different from controls. In mice tested with i.t. administration of CGS-12066A, none of the oligo treatments produced a significant attenuation of analgesia. In mice tested with i.t. administration of 2-methyl-5-HT, only 5-HT3 receptor AODN attenuated analgesia. Thus, 5-HT and 2-methyl-5-HT analgesia are mediated by the 5-HT3 receptor subtype. However, spinal CGS-12066A analgesia appears not to be mediated by either the 5-HT1B or the 5-HT3 receptor subtypes.
Paul
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The Department of Pharmacology and Experimental Therapeutics and Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA. dpaul@lsuhsc.edu
Yao
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D
Zhu
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Minor
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LD
Garcia
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D000818:Animals; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009619:Nociceptors / Q000187:drug effects*; D020319:Oligodeoxyribonucleotides, Antisense; D010147:Pain Measurement / Q000187:drug effects*; D011810:Quinoxalines / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013116:Spinal Cord / Q000502:physiology*
D020319:Oligodeoxyribonucleotides, Antisense; D011810:Quinoxalines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; C052561:CGS 12066B; D012701:Serotonin; C045918:2-methyl-5-HT