Vol. 298, Issue 2, 674-678, August 2001

5-Hydroxytryptamine₃ (5-HT₃) Receptors Mediate Spinal 5-HT Antinociception: An Antisense Approach

Dennis Paul, Dongdong Yao, Peimin Zhu, Lerna D. Minor and Meredith Mason Garcia

The Department of Pharmacology and Experimental Therapeutics and Neuroscience Center of Excellence, Louisiana State University Health Sciences Center (D.P., D.Y., P.Z., L.D.M.); and Department of Otolaryngology, Tulane University Medical College (M.M.G.), New Orleans, Louisiana

To examine the role of the 5-hydroxytryptamine_1B (5-HT_1B) 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-HT_1B 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-HT_1B 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-HT_1B or the 5-HT₃ receptor subtypes.