Interplay between 5-HT2C and 5-HT1A receptors in the dorsal periaqueductal gray in the modulation of fear-induced antinociception in mice

Abstract

The confinement of rodents to the open arm of the elevated-plus maze provokes antinociception (OAA). As a type of defensive reaction, the OAA has been investigated through systemic and intramesencephalic (e.g., dorsal portion of the periaqueductal gray - dPAG) injections of anxiolytic-like drugs [e.g., serotonergic (5-HT) receptor agonists or antagonists]. Here we investigated the effects of (i) intra-dPAG injections of a 5HT receptor agonist (MK-212; 0.21 or 0.63 nmol) and antagonist (SB 242084; 0.01, 0.1 or 1.0 nmol); (ii) combined injections of SB 242084 and MK-212 into the dPAG; (iii) combined injections of SB 242084 with 8-OHDPAT (10 nmol) into the dPAG on the OAA in male Swiss mice. Nociception was assessed with the writhing test induced by acetic acid injection. Results showed that (i) intra-dPAG injection of MK-212 (0.63 nmol) increased the OAA; (ii) intra-dPAG SB 242084 (1.0 nmol) prevented the OAA; (iii) SB 242084 (0.1 nmol, a dose devoid of intrinsic effect on nociception) blocked the OAA enhancement provoked by MK-212 and enabled 8-OH-DPAT to prevent the OAA. These results suggest that OAA is mediated by 5-HT receptors within the dPAG. Intra-dPAG SB242084 administration provoked similar results on the effects produced by MK-212 and 8-OH-DPAT on OAA. In addition, the dPAG 5-HT and 5-HT receptors interact each other in the modulation of OAA.

Chronic Fluoxetine Impairs the Effects of 5-HT1A and 5-HT2C Receptors Activation in the PAG and Amygdala on Antinociception Induced by Aversive Situation in Mice

“…Similarly to the results obtained in the amygdala, experiment 5 showed that intra-PAG injection of MK-212 also intensified OAA, an effect that corroborates previous studies (e.g., Baptista et al, 2012;Baptista-de-Souza et al, 2018). Again, activation of 5-HT 2C receptors in the PAG selectively enhanced OAA without changing nociceptive response in EA-confined animals.…”

“…8-OH-DPAT [(±)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide; Sigma, (10 nmol)] (5-HT 1A receptor agonist); MK-212 [6-chloro-2-(1-piperazinyl)] pyrazine hydrochloride, Tocris Cookson Inc. (0.63 nmol) (5-HT 2C receptor agonist). Doses used for the intra-amygdala and intra-PAG treatments were based on previous studies (Nunes- de-Souza et al, 2000;Gomes and Nunes-De-Souza, 2009;Vicente and Zangrossi, 2012;Baptista-de-Souza et al, 2018;Tavares et al, 2018). The doses were prepared in saline or vehicle (physiological saline with 2 % of Tween 80) and a final volume of 0.1 µl was injected.…”

“…The influence of emotional states such as anxiety and fear on pain reaction has been widely investigated in animal models (Siegfried et al, 1990;Fields, 2004;Baptista et al, 2009;Furuyada-Cunha et al, 2016) and the exposure to the elevated plusmaze (EPM), a widely used animal model of anxiety (Lister, 1987;Carobrez and Bertoglio, 2005) has been employed to investigate the underlying mechanisms of the anxiety/fearinduced antinociception phenomenon (Lee and Rodgers, 1990). In this context, previous studies have been showing the role of serotonin at 5-HT 1A and 5-HT 2C receptors in the modulation of the antinociception induced by the EPM open-arm confinement (OAA) in mice (Nunes- de-Souza et al, 2000;Baptista-de-Souza et al, 2018;Tavares et al, 2018).…”

Pharmacological interaction between NSAIDS with clomipramine and risperidone in mice visceral pain

“…(Baptista‐de‐Souza, Pelarin, Canto‐de‐Souza, Nunes‐de‐Souza, & Canto‐de‐Souza, ; Miranda et al, ; Miranda & Pinardi, ; Zygmunt, Chłoń‐Rzepa, & Sapa, ). The power order obtained is related to the inhibitory activity of COX‐2, COX‐1, and COX‐3, respectively.…”

Network Neuromodulation of Opioid and GABAergic Receptors Following a Combination of “Juvenile” and “Adult Stress” in Rats

“…Several neurotransmitters are involved in the transmission of signals to and from the PAG. Specifically, GABAergic receptors are involved in descending pain control pathways, mediated by interneurons [ 56 ]. It was shown that stimulation of 5-HT on GABAergic neurons in the vPAG demonstrates anxiolysis [ 57 ].…”