The role of dorsomedial and ventrolateral columns of the periaqueductal gray matter and in situ 5-HT_2Aand 5-HT_2Cserotonergic receptors in post-ictal antinociception

Abstract

The periaqueductal gray matter (PAG) consists in a brainstem structure rich in 5-hydroxytryptamine (5-HT) inputs related to the modulation of pain. The involvement of each of the serotonergic receptor subtypes found in PAG columns, such as the dorsomedial (dmPAG) and the ventrolateral (vlPAG) columns, regarding post-ictal antinociception have not been elucidated. The present work investigated the participation of the dmPAG and vlPAG columns in seizure-induced antinociception. Specifically, we studied the involvement of serotonergic neurotransmission in these columns on antinociceptive responses that follow tonic-clonic epileptic reactions induced by pentylenetetrazole (PTZ), an ionophore GABA-mediated Cl(-) influx antagonist. Microinjections of cobalt chloride (1.0 mM CoCl2 /0.2 µL) into the dmPAG and vlPAG caused an intermittent local synaptic inhibition and decreased post-ictal antinociception that had been recorded at various time points after seizures. Pretreatments of the dmPAG or the vlPAG columns with the nonselective serotonergic receptors antagonist methysergide (5.0 µg/0.2 µL) or intramesencephalic microinjections of ketanserin (5.0 µg/0.2 µL), a serotonergic antagonist with more affinity to 5-HT2A/2C receptors, decreased tonic-clonic seizure-induced antinociception. Both dmPAG and vlPAG treatment with either the 5-HT2A receptor selective antagonist R-96544 (10 nM/0.2 µL), or the 5-HT2C receptors selective antagonist RS-102221 (0.15 µg/0.2 µL) also decrease post-ictal antinociception. These findings suggest that serotonergic neurotransmission, which recruits both 5-HT2A and 5-HT2C serotonergic receptors in dmPAG and vlPAG columns, plays a critical role in the elaboration of post-ictal antinociception.

Role of TRPV1 channels of the dorsal periaqueductal gray in the modulation of nociception and open elevated plus maze-induced antinociception in mice

“…It is noteworthy, however, that many other neurotransmitter systems (e.g., serotonin [52], opioids [53,54], cannabinoids [17,55], etc.) located within the PAG have also been implicated in the modulation of nociception and various forms of stress-induced antinociception.…”

Blockade of Cannabinoid CB1 Receptors in the Dorsal Periaqueductal Gray Unmasks the Antinociceptive Effect of Local Injections of Anandamide in Mice

“…In this context, several neurotransmitters have been implicated mediating nociception, for instance, opioids (Yaksh and Noueihed, 1985; Jensen and Yaksh, 1989; Cornelio and Nunes-de-Souza, 2009; Morgan et al, 2014), glutamate (Yaksh and Noueihed, 1985; Palazzo et al, 2013; Wilson-Poe et al, 2013), serotonin (Eschalier et al, 1989; Baptista-de-Souza et al, 2014; de Freitas et al, 2014), and endocannabinoids (Meng et al, 1998; Suplita et al, 2005; Olango et al, 2012). More recently, vanilloid compounds, which are known to activate the Transient Receptor Potential Vanilloid – type 1 (TRPV1) channels, emerged as an important neurotransmission system modulating nociception (e.g., McGaraughty et al, 2003; Starowicz et al, 2007; Mascarenhas et al, 2015).…”

Ictal analgesia in temporal lobe epilepsy – The mechanism of seizure-related burns

“…Henceforth, efforts have been made to elucidate the impact of 5HT 2A/2C receptors in the organization of postictal antinociception [13,16,34,35] and the recruitment of 5-HT 1A/1B , 5-HT 6 , 5-HT 7 receptor subtypes has been demonstrated [36].…”