5‐HT_1B receptors inhibit glutamate release from primary afferent terminals in rat medullary dorsal horn neurons

Abstract

Primary afferent-evoked EPSCs were recorded from medullary dorsal horn neurons of rat horizontal brain stem slices using a conventional whole-cell patch clamp technique under a voltage-clamp condition. KEY RESULTSCP93129, a selective 5-HT1B receptor agonist, reversibly and concentration-dependently decreased the amplitude of glutamatergic EPSCs and increased the paired-pulse ratio. In addition, CP93129 reduced the frequency of spontaneous miniature EPSCs without affecting the current amplitude. The CP93129-induced inhibition of EPSCs was significantly occluded by GR55562, a 5-HT1B/1D receptor antagonist, but not LY310762, a 5-HT1D receptor antagonist. Sumatriptan, an anti-migraine drug, also decreased EPSC amplitude, and this effect was partially blocked by either GR55562 or LY310762. On the other hand, primary afferent-evoked EPSCs were mediated by the Ca 2+ influx passing through both presynaptic N-type and P/Q-type Ca 2+ channels. The CP93129-induced inhibition of EPSCs was significantly occluded by w-conotoxin GVIA, an N-type Ca 2+ channel blocker. CONCLUSIONS AND IMPLICATIONSThe present results suggest that the activation of presynaptic 5-HT1B receptors reduces glutamate release from primary afferent terminals onto medullary dorsal horn neurons, and that 5-HT1B receptors could be, at the very least, a potential target for the treatment of pain from orofacial tissues. Abbreviations w-AgTx, w-agatoxin IVA; APV, DL-2-amino-5-phosphonovaleric acid; w-CgTx, w-conotoxin GVIA; CP93129, 3-(1,2,3,6-tetrahydropyridin-4-yl)-1,4-diydropyrrolo[3,2-b]pyridine-5-one; GIRK, G-protein-coupled inwardly rectifying K LINKED ARTICLE

Enzymatic conversion of ATP to adenosine contributes to ATP-induced inhibition of glutamate release in rat medullary dorsal horn neurons

“…The conduction velocity of primary afferents innervating medullary dorsal horn neurons was calculated by dividing the distance between stimulation and recording sites by the latency of EPSCs (see Choi et al, 2012). The effect of drugs on EPSCs was quantified as a percentage change in EPSC amplitude compared to the control values.…”

“…All electrophysiological experiments were performed at room temperature (22e25 C). To record action potential-dependent glutamatergic excitatory postsynaptic currents (EPSCs), a glass stimulation pipette (~10 mm diameter) filled with a bath solution, was positioned around the trigeminal root (see Choi et al, 2011Choi et al, , 2012. Brief paired pulses (500 ms, 1e5 V, 20 Hz) were applied by the stimulation pipette at a frequency of 0.1 Hz using a stimulator (SEN-7203, Nihon Kohden, Tokyo, Japan) equipped with an isolator unit (SS-701J, Nihon Kohden).…”

Serotonin gating of cortical and thalamic glutamate inputs onto principal neurons of the basolateral amygdala

“…Our results are consistent with previous studies showing that 5-HT decreased glutamatergic transmission in multiple brain regions including the BLA (Cheng et al, 1998, Rainnie, 1999, Yamamoto et al, 2012). However depending on the brain region examined, the inhibitory effect of 5-HT was reported to be mediated by 5-HT 1A receptors (Costa et al, 2012, Ostrowski et al, 2014), 5-HT 1B receptors (Singer et al, 1996, Laurent et al, 2002, Lemos et al, 2006, Choi et al, 2012), or both (Bouryi and Lewis, 2003). …”

Optogenetic Recruitment of Dorsal Raphe Serotonergic Neurons Acutely Decreases Mechanosensory Responsivity in Behaving Mice

“…Among these, serotonergic neuromodulation has long been implicated in the inhibition of sensory responsivity [5], [6], an idea chiefly supported by gain-of-function experiments. Pharmacological enhancement of 5-HT function inhibits primary afferent neurotransmission in vitro [7], [8], dampens sensory and nociceptively-evoked firing in vivo [9]-[11], [12] and decreases acoustic startle responses and their pre-pulse inhibition [6], [13]. Similarly, electrical microstimulation of the dorsal raphe nucleus (DRN), one of the largest sources of ascending 5-HT projections [14], reduces forebrain sensory and nociceptively-evoked activity [9], [11], [12], [15]–[17] and elevates vocalization thresholds to noxious stimuli [18].…”