The μ1-opioid receptor and 5-HT2A- and 5HT2C-serotonergic receptors of the locus coeruleus are critical in elaborating hypoalgesia induced by tonic and tonic–clonic seizures

•Peripheral blockade of GABAA receptors evoke tonic–clonic seizures.•Seizing animals display antinociceptive process.•Transitory synaptic blockade into the LC decreases post-ictal antinociception.•LC μ1-Opioid receptors mediate post-ictal antinociception.•LC 5-HT2A- and 5-HT2C-serotonergic receptors modulate post-ictal antinociception.

It has been proposed that the post-ictal state is associated with the expression of hypoalgesia. It is clear that the projections among the periaqueductal gray matter (PAG), dorsal raphe nucleus (DRN) and locus coeruleus (LC) play a role in pain management. These mesencephalic structures have direct reciprocal opioid and monoaminergic projections to the LC that can possibly modulate post-ictal hypoalgesia. The goal of this study was to examine if LC-opioid and serotonergic/noradrenergic mechanisms signal the post-ictal hypoalgesic responses to tonic–clonic seizures produced by intraperitoneal administration of pentylenetetrazole (PTZ at 64 mg/kg), causing an ionophore γ-aminobutyric acid (GABA)-mediated Cl− influx antagonism. The rodents’ nociceptive threshold was measured by the tail-flick test. Intra-LC cobalt chloride (1.0 nM/0.2 μL) microinjections produced intermittent local synaptic inhibition and were able to reduce post-ictal hypoalgesia. Central administration of naltrexone (a non-selective antagonist for opioid receptors), naloxonazine (a selective antagonist for μ1-opioid-receptors), methysergide (a non-selective antagonist for serotonergic receptors) or ketanserin (an antagonist for both α1-noradrenergic and 5-Hydroxytryptamine(HT)2A/2C receptors) at 5.0 μg/0.2 μL, R-96544 (a 5-HT2A receptor selective antagonist) at 10 nM/0.2 μL, or RS-102221 (a 5-HT2C receptor selective antagonist) at 0.15 μg/0.2 μL into the LC also decreased post-ictal hypoalgesia. The data presented here suggest that the post-ictal antinociception mechanism involves the μ1-opiod, 5-HT2A- and 5-HT2C-serotonergic, and α1-noradrenergic receptors in the LC.