Paradoxical effect of noradrenaline-mediated neurotransmission in the antinociceptive phenomenon that accompanies tonic–clonic seizures: Role of locus coeruleus neurons and α2- and β-noradrenergic receptors

Abstract

The postictal state is generally followed by antinociception. It is known that connections between the dorsal raphe nucleus, the periaqueductal gray matter, and the locus coeruleus, an important noradrenergic brainstem nucleus, are involved in the descending control of ascending nociceptive pathways. The aim of the present study was to determine whether noradrenergic mechanisms in the locus coeruleus are involved in postictal antinociception. Yohimbine (an α(2)-receptor antagonist) or propranolol (a β-receptor antagonist) was microinjected unilaterally into the locus coeruleus, followed by intraperitoneal administration of pentylenetetrazole (PTZ), a noncompetitive antagonist that blocks GABA-mediated Cl(-) influx. Although the administration of both yohimbine and propranolol to the locus coeruleus/subcoeruleus area resulted in a significant decrease in tonic or tonic-clonic seizure-induced antinociception, the effect of yohimbine restricted to the locus coeruleus was more distinct compared with that of propranolol, possibly because of the presynaptic localization of α(2)-noradrenergic receptors in locus coeruleus neurons. These effects were related to the modulation of noradrenergic activity in the locus coeruleus. Interestingly, microinjections of noradrenaline into the locus coeruleus also decrease the postictal antinociception. The present results suggest that the mechanism underlying postictal antinociception involves both α(2)- and β-noradrenergic receptors in the locus coeruleus, although the action of noradrenaline on these receptors causes a paradoxical effect, depending on the nature of the local neurotransmission.

Neuroanatomical and neuropharmacological approaches to postictal antinociception‐related prosencephalic neurons: the role of muscarinic and nicotinic cholinergic receptors

“…, , ; Felippotti et al. ). Thus, the outputs to the dH from the endogenous pain modulatory system nuclei shown in this study may reflect their involvement in postictal antinociception through the modulation of the activity of hippocampal outputs.…”

“…We have previously shown that the DRN and its serotonergic receptors, as well as the LC and its noradrenergic receptors, are key structures in the pain endogenous modulatory system recruited during postictal antinociception Freitas et al 2005Freitas et al , 2008Freitas et al , 2009Felippotti et al 2011a). Thus, the outputs to the dH from the endogenous pain modulatory system nuclei shown in this study may reflect their involvement in postictal antinociception through the modulation of the activity of hippocampal outputs.…”

“…; Felippotti et al. ,b, ). At low doses, PTZ causes absence seizures (Snead ), while intermediate doses lead to clonic seizures.…”

“…Pentylenetetrazole (PTZ), a gamma amino butyric acid (GABA)ergic receptor antagonist, is commonly used in adult rodents to generate generalized seizure-based animal models of epilepsy (Meilleur et al 2003;de Freitas et al 2004;Freitas et al 2005Freitas et al , 2008Freitas et al , 2009De Oliveira et al 2011;Felippotti et al 2011aFelippotti et al ,b, 2012. At low doses, PTZ causes absence seizures (Snead 1992), while intermediate doses lead to clonic seizures.…”

The beneficial effects of meditation: contribution of the anterior cingulate and locus coeruleus

“…Fear-induced antinociception also occurs via LC pathways (Biagioni et al, 2013), seizure-induced antinociception involves LC alpha 2 and beta adrenergic receptors (Felippotti et al, 2011) and the LC is thought to play a role in the antinociception caused by stimulation of the motor cortex (Viisanen and Pertovaara, 2010). …”