5-HT1A receptors and the tail-flick response. IV. Spinally localized 5-HT1A receptors postsynaptic to serotoninergic neurones mediate spontaneous tail-flicks in the rat

The present study examined the location of the serotonin (5-HT)1A receptors mediating the induction of spontaneous tail-flicks (STFs) in the rat. Serotoninergic neurones were lesioned by i.c.v. administration of 5,7-dihydroxytryptamine, which depleted levels of 5-HT in the spinal cord and other CNS tissues by90% without affecting those of noradrenaline and dopamine. In lesioned rats, the ability of the 5-HT releasers, para-chloroamphetamine and methylenedioxymethamphetamine, to elicit STFs was abolished. In contrast, the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)- tetralin (8-OH-DPAT), continued to evoke STFs. In fact, its effect was significantly enhanced in lesioned as compared with sham animals. In (nonlesioned) rats with catheters chronically implanted at the lumbar spinal level, intrathecal 8-OH-DPAT dose-dependently evoked STFs. The action of 8-OH-DPAT was extremely rapid, being maximal within 1 min of injection. Whereas the 5-HT1B/C agonist, TFMPP, the 5-HT1C/2 agonist, DOI, and the 5-HT3 agonist, m-chlorophenylbiguanide, failed to elicit STFs, the action of 8-OH-DPAT was mimicked by several other 5-HT1A agonists: S 14671, 5-MeODMT and lisuride. These also showed a time-course with a rapid onset. Further, the highly hydrophilic 5-HT1A agonist, 5-carboxyamidotryptamine, which fails to pass the blood-brain barrier, likewise dose-dependently elicited STFs upon direct lumbar administration. In contrast, administered onto the cervical spinal cord, it was completely ineffective. Systemic administration of the 5-HT1A antagonists, BMY 7378 or (-)-alprenolol, but not of the 5-HT1C/2 antagonist, ritanserin, nor of the 5-HT3 antagonist, ondansetron, blocked STFs elicited by lumbar administration of 8-OH-DPAT. Conversely, lumbar (but not cervical) administration of BMY 7378 and (-)-alprenolol dose-dependently blocked the action of systemic 8-OH-DPAT. These data demonstrate that STFs in the rat are mediated by 5-HT1A receptors postsynaptic to 5-HT neurones and localized in the lumbar spinal cord. Further, they support the concept of a relationship between STFs and mechanisms of primary sensory (nociceptive) processing.