Persistent peripheral inflammation and pain induces immediate early gene activation in supraspinal nuclei in rats.

Pain is a public health concern worldwide and can present simultaneously with anxiety and depression. c-Fos is a marker used to identify activated cells in response to various stimuli. Specifically, it can be used as a brain marker of pain. We examined whether peripheral inflammation produces mechanical allodynia, anxiety- and depression-related behaviors in male rats (Rattus norvegicus, Wistar strain) and if these behaviors can have an impact on c-Fos expression in the supraspinal nuclei involved in pain control. We assessed mechanical thresholds by von Frey monofilaments, depression-like behaviors in the forced swimming test (FST) and anxiety-related behaviors in the open field test (OFT) after the administration of the inflamogen Complete Freund´s Adjuvant (CFA) in rats. We found that CFA increased paw diameter is all rats, however, CFA treatment resulted in a subgroup of rats developing allodynia [CFA- mechanical allodynia (CFA-MA)] and a subgroup of rats not developing allodynia [CFA-no mechanical allodynia (CFA-NMA)]. The peak of tactile allodynia and inflammation were coupled with an increase in c-Fos expression in several supraspinal brain nuclei, i.e. basolateral amygdala, periaqueductal gray matter and rostroventromedial medulla in CFA-MA rats. Moreover, we found a correlation between c-Fos levels and mechanical thresholds. No modification in c-Fos expression was observed in CFA-NMA rats. CFA did not modulate behaviors in the OFT or FST. In summary, we show that mechanical allodynia but not peripheral inflammation activates c-Fos in several supraspinal nuclei, which sheds new light on brain regions involved in the control of pain following peripheral injury and decouples this effect from mere peripheral inflammation. This model may be used to study resistance to pain development in future studies.

A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT2A, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT2A ß-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT2A-selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications.