Maternal separation increases pain sensitivity by reducing the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus.

Animals subjected to early life maternal separation exhibit increased sensitivity to chemical, thermal, and mechanical stimuli during adulthood. However, the mechanism by which maternal separation can alter pain sensitivity in adulthood has not yet been investigated. Thus, we aimed to evaluate the activity of serotonergic and noradrenergic neurons and the effect of serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors in male and female Wistar rats subjected to maternal separation. This study consisted of two experiments: 1) to confirm whether maternal separation increased pain sensitivity (n = 8 per group) and to evaluate the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus in animals subjected to maternal separation in comparison to controls (n = 6 per group); and 2) to evaluate the effect of fluoxetine (a selective 5-HT reuptake inhibitor) and desipramine (a NA reuptake inhibitor) on sensitivity to chemical stimulation using formalin in animals subjected to maternal separation (n = 8 per group). Our findings indicated that maternal separation increases an animal's sensitivity to painful chemical stimulation and reduces the activity of 5-HT and NA neurons. In addition, acute pretreatment with a 5-HT or NA reuptake inhibitor prevented the increased response to painful stimulation induced by maternal separation. In conclusion, maternal separation increases pain sensitivity by reducing the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus. This study contributes to possible treatments for pain in individuals exposed to early life stress.

3-Hydroxy-piperidinyl-N-benzyl-acyl-arylhydrazone derivatives reduce neuropathic pain and increase thermal threshold mediated by opioid system.

Here in, we report the preparation and evaluation of four 3-hydroxy-piperidine-N-benzyl-aryl-acylhydrazone derivatives (6a-d) for their potential antinociceptive activity. In the tail flick test, compounds 6a and 6d exhibited a significant increase in the latency time of the animals, in comparison to the control group. These two compounds also showed a significant increase in the nociceptive threshold from 1 to 6 h after treatment in the CCI neuropathic pain model. In both cases, the antinociceptive activity was blocked by naloxone, suggesting an opioid mechanism of action, but without sedative or motor coordination effects.

Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer's disease.

A novel series of feruloyl-donepezil hybrid compounds were designed, synthesized and evaluated as multitarget drug candidates for the treatment of Alzheimer's Disease (AD). In vitro results revealed potent acetylcholinesterase (AChE) inhibitory activity for some of these compounds and all of them showed moderate antioxidant properties. Compounds 12a, 12b and 12c were the most potent AChE inhibitors, highlighting 12a with IC50 = 0.46 µM. In addition, these three most promising compounds exhibited significant in vivo anti-inflammatory activity in the mice paw edema, pleurisy and formalin-induced hyperalgesy models, in vitro metal chelator activity for Cu2+ and Fe2+, and neuroprotection of human neuronal cells against oxidative damage. Molecular docking studies corroborated the in vitro inhibitory mode of interaction of these active compounds on AChE. Based on these data, compound 12a was identified as a novel promising drug prototype candidate for the treatment of AD with innovative structural feature and multitarget effects.