5-HT3 receptor within the amygdaloid complex modulates pain hypersensitivity induced by empathy model of cohabitation with a partner in chronic pain condition in mice.

Cohabitation with a partner undergoing chronic pain induces pain hypersensitivity. Among a lot of other neurochemical pathways, the serotonin (5-HT) role, specifically the 5-HT3 receptor (5-HT3R), in the amygdala has never been evaluated in this model. Here we studied the effects of the amygdala's chemical inhibition, its neuronal activation pattern, and 5-HT, 5-HIAA, and 5-HT turnover within the amygdala. Furthermore, the systemic and intra-amygdala 5-HT3R activation and blockade in mice that cohabited with a conspecific subjected to chronic constriction injury were investigated. Male Swiss mice were housed in partners for 28 days. The dyads were divided into two groups on the 14th day: cagemate nerve constriction (CNC) and cagemate sham (CS). On the 24th day, cagemates underwent a stereotaxic surgery (when necessary) and, on the 28th day, they were evaluated on the writhing test. The amygdala inactivation promotes pain-hypersensitivity behaviors in groups and dyads; cohabitation with a partner with chronic pain did not change FosB-labeled cells in the amygdala's nucleus and increases 5-HT turnover in cagemates. Systemic and intra-amygdala 5-HT3R activation attenuated and enhanced the number of writhes, respectively. In contrast, 5-HT3R blockade reduced hypersensitivity pain response. Results suggest the involvement of amygdala serotonergic signaling via 5-HT3R in empathy-like behavior.

Empathy for Pain: Insula Inactivation and Systemic Treatment With Midazolam Reverses the Hyperalgesia Induced by Cohabitation With a Pair in Chronic Pain Condition.

Empathy for pain is the ability to perceive and understand the pain in the other individual. Recent studies suggested that rodents have this social ability. GABAergic system has receptors in the brain structures involved in emotional processes as well as in the insular cortex. This area has been described as an important key in modulation of pain and empathy. The present study has investigated the role of insula and its Benzodiazepine-GABAA system on social modulation of pain induced by cohabiting with a mouse submitted to sciatic nerve constriction, a neuropathic pain model. The insular cortex function was assessed by the structure inactivation (Experiments 1 and 2); the role of GABA system was evaluated by systemic treatment of midazolam (MDZ 0.5, 1, and 2 mg/kg) (Experiment 3); and the role of GABAA receptors of insula were studied by bilateral MDZ (3 and 30 nmol/0.1 µl) microinjections in the structure (Experiment 4). Male Swiss mice were housed in groups or dyads. On dyads, after 14 days of cohabitation they were divided into two groups: cagemate nerve constriction and cagemate sham (CS). After 14 days of familiarity, cagemates were evaluated on the writhing test. For group-housed, insula inactivation did not change nociception. For dyad-housed, cohabiting with a mouse in chronic pain increased the nociceptive response and the insula inactivation has reverted this response. Systemic MDZ attenuated nociception and intra-insula MDZ did not alter it. Our results suggest that cohabitation with a pair in chronic pain induces hypernociception, insula possibly modulates this response and the GABA system is also possibly involved, but not its insular mechanisms.

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

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 5HT2C 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-HT2C 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-HT1A and 5-HT2C receptors interact each other in the modulation of OAA.