The Role of 5-Hydroxytryptamine₃ Receptors in the Vagal Afferent Activation-Induced Inhibition of the First Cervical Dorsal Horn Spinal Neurons Projected from Tooth Pulp in the Rat

Abstract

To test the hypothesis that vagal afferent (VA) stimulation modulates the first cervical dorsal horn (C 1 ) neuron activity, which is projected by tooth pulp (TP) afferent inputs through the activation of a local GABAergic mechanism via 5-hydroxytryptamine 3 (5-HT 3 ) receptors, we used the technique of microiontophoretic application of drugs. In pentobarbitalanesthetized rats, we recorded C 1 spinal neuron activity responding to TP stimulation. The TP stimulation-evoked C 1 spinal neuron excitation was inhibited by VA stimulation, and this inhibition was significantly attenuated by iontophoretic application of the 5-HT 3 receptor antagonist ICS 205-930 (3-tropanyl-indole-3-carboxylate hydrochloride [endo-8-methyl-8-azabicyclo [3.2.1] oct-3-ol indol-3-yl-carboxylate hydrochloride]) (40 nA) or the GABA A receptor antagonist bicuculline (40 nA). In another series of experiments, we determined that 60 nA iontophoretic application of glutamate produced a maximal increase in the C 1 spinal neuron activity at a minimal current. In 53 of 65 neurons (81.5%), VA conditioning stimulation (1.0 mA ϫ 0.1 ms, 50 Hz for 30 s) caused a significant inhibition (35.1%) of the glutamate (60 nA) application-evoked C 1 spinal neuron excitation. Iontophoretic application of ICS 205-930 (40 nA) or bicuculline (40 nA) significantly attenuated the VA stimulation-induced inhibition of glutamate iontophoretic application (60 nA)-evoked C 1 spinal neuron excitation. These results suggest that VA stimulation-induced suppression of C 1 spinal neuron activity, responding to TP stimulation, involve 5-HT 3 receptor activation, possibly originating in the descending serotonergic inhibitory system, and postsynaptic modulation of inhibitory GABAergic neurons.The trigeminal spinal nucleus is considered to be closely associated with the perception and transmission of orofacial sensory information, including nociceptive signals from tooth pulp (TP) (Strassman and Vos, 1993;Iwata et al., 1998). The trigeminal spinal nucleus is functionally and anatomically subdivided into three nuclei: oralis, interpolaris, and caudalis (Sessle, 1987). The subnucleus caudalis (spVc) is thought to be analogous to the spinal dorsal horn (Hu et al., 1981), and the histological structures of the first cervical dorsal horn (C 1 ) have an analogy to the spVc. From these observations, it is possible to speculate that certain inputs from TP afferent fibers terminate in the C 1 segment of the spinal cord. This possibility was confirmed by evidence that C 1 spinal neurons responded to electrical stimulation of the TP Takeda et al., 1999;Tanimoto et al., 2002). Furthermore, we reported that both N-methyl-D-aspartate (NMDA) and non-NMDA receptors contribute to excitation of the C 1 spinal neuron activity evoked by TP stimulation . These results led us to suggest that C 1 spinal neurons process nociceptive information carried in the trigeminal nerve from the TP, and this involves excitatory glutaminergic mechanisms.Vagal afferent (VA) inputs play an important role in the re...

Inhibition of Trigeminal Nociception by Non-invasive Vagus Nerve Stimulation: Investigating the Role of GABAergic and Serotonergic Pathways in a Model of Episodic Migraine

“…The activation of 5-HT 3 and 5-HT 7 receptors on inhibitory neurons by nVNS would enhance the descending inhibitory pain pathway via activation of spinal interneurons and release of the inhibitory neurotransmitters, GABA and glycine, to suppress ascending pain transmission. This mechanism is supported by other orofacial pain studies involving trigeminal nerve activation in which direct stimulation of the vagus nerve was shown to exhibit anti-nociceptive effects, to facilitate the serotonergic descending inhibition pathway, and to modulate inhibition of GABAergic neurons (14,40,41). Other mechanisms may also be involved in nVNS inhibition of trigeminal pain signaling.…”

“…In contrast, the inhibitory effect of nVNS as an acute migraine treatment is proposed to promote multiple distinct cellular changes and pathways within the brain and spinal cord to facilitate descending pain modulation (13). The descending inhibitory pathway is known to involve activation of 5-HT3 and 5-HT7 receptors on inhibitory interneurons that stimulates release of glycine and GABA, which act as inhibitory neurotransmitters of primary or secondary trigeminal nociceptors (14). Thus, the reported efficacy of nVNS may involve modulation of GABAergic and serotonergic signaling but this pathway has not been demonstrated in episodic migraine models.…”

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

“…It is well documented that anesthetics enhance GABA A receptor mediated synaptic currents, thus increasing the inhibitory drive in neuronal networks. However, it has to be remembered that 5-HT 3 receptors are located on some inhibitory GABAergic interneurons in the amygdala (Koyama et al, 2000), cortex (Zhou and Hablitz, 1999;Puig et al, 2004), hippocampus (McMahon and Kauer, 1997), and spinal cord (Alhaider et al, 1991;Tanimoto et al, 2004) and can control the release of GABA into the synapse, presumably through Ca 2ϩ -permeable homomeric 5-HT 3A receptors (Koyama et al, 2000). Hence, anesthetic modulation of 5-HT 3 receptors in these areas will affect GABA release and change the in- Recently, a study showed that 5-HT 3 receptor antagonists reduce the halothane-mediated inhibition of spinal dorsal horn sensory neuronal responses to noxious peripheral stimulation, indicating that 5-HT 3 receptors are anesthetic targets for the reduction in nociception (Koshizaki et al, 2003).…”

The dietary constituent resveratrol suppresses nociceptive neurotransmission via the NMDA receptor

“…The technique of iontophoretic application was the same as described in our previous reports. 17,18,25,31 One of the two lateral barrels of the micropipette contained 160 mmol/L NaCl which was used for balancing currents to prevent the occurrence of tip polarization artifacts. The remaining lateral barrel contained NMDA (200 mmol/L in 160 mmol/L NaCl, pH 8.5) or L-glutamate (100 mmol/L in 160 mmol/L NaCl, pH 8.5; Nacalai Tesque, Kyoto, Japan), as described previously.…”