Modulation of afferent-evoked neurotransmission by 5-HT₃ receptors in young rat dorsal horn neurones in vitro: A putative mechanism of 5-HT₃ induced anti-nociception

1. The in vitro hemisected spinal cord from young rat was used to investigate the mechanism of serotoninergic modulation of primary afferent-mediated synaptic transmission in the dorsal horn through activation of the 5-HT₃ receptor. 2. Dorsal root-evoked excitatory post-synaptic potentials (DR-EPSPs) were recorded intracellularly from dorsal horn neurones. Extracellular recordings of the population primary afferent depolarization (PAD) and the dorsal root-evoked dorsal root reflex (DR-DRR) were made from segmental dorsal roots. 3. 5-Hydroxytryptamine (5-HT) and the selective 5-HT₃ receptor agonist l-(m-chloro-phenyl)biguanide hydrochloride (m-ChPB) (10 and 50 μM) induced statistically significant reductions of the DR-EPSP amplitude (P < 0.001) and duration (P < 0.001) in the majority of dorsal horn neurones. The 5-HT₃ receptor selective antagonists 3-Tropanyl-indole-3-carboxylate hydrochloride (Tropisetron, 10 μM) and N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4 -benzoxazine-8-carboxamide (Y-25130, 10 μM) abolished m-ChPB-induced DR-EPSP attenuation and partially blocked the 5-HT effect. 4. m-ChPB (50 μM)-induced DR-EPSP amplitude and duration attenuation was retained in the presence of the GABA(A) receptor antagonist bicuculline (30 μM), the GABA(B) receptor antagonist saclofen (50 μM) and the opioid receptor antagonist naloxone (50 μM). 5. Both 5-HT and m-ChPB (10 and 50 μM) induced a PAD but the mean peak amplitude of 5-HT-induced PAD was significantly greater than PAD to m-ChPB (98.6 ± 12 μV compared to 51.8 ± 10 μV for 50 μM of agonist, respectively). Tropisetron partially reduced 5-HT-induced PAD and abolished m-ChPB-induced PAD. 5-HT, but not m-ChPB, significantly (P < 0.001) reduced the peak amplitude of the DR-DRR and this action of 5-HT was unaffected by Tropisetron or Y-25130. 6. These data provide experimental evidence for a putative cellular mechanism at the level of the dorsal horn for anti-nociceptive effects of 5-HT₃ receptor activation. This 5-HT₃-mediated modulation of sensory afferent transmission was evidently independent of inhibitory GABA- or opioid-dependent interneuronal pathways. The extent to which the 5-HT₃ receptor could be involved in the operation of endogenous analgesia and sensory modulation by descending monoamine bulbospinal pathways is discussed.