5-O-methylcneorumchromone K Exerts Antinociceptive Effects in Mice via Interaction with GABAA Receptors.

Luiza Carolina França Opretzka,Marcelo Santos Castilho,Josean Fechine Tavares,Renan Fernandes Espírito-Santo,Iura Muniz Alves,Eudes Da Silva Velozo,Lucas Silva Abreu,Cristiane Flora Villarreal,Humberto Fonseca De Freitas

doi:10.3390/ijms22073413

Abstract

The proper pharmacological control of pain is a continuous challenge for patients and health care providers. Even the most widely used medications for pain treatment are still ineffective or unsafe for some patients, especially for those who suffer from chronic pain. Substances containing the chromone scaffold have shown a variety of biological activities, including analgesic effects. This work presents for the first time the centrally mediated antinociceptive activity of 5-O-methylcneorumchromone K (5-CK). Cold plate and tail flick tests in mice showed that the 5-CK-induced antinociception was dose-dependent, longer-lasting, and more efficacious than that induced by morphine. The 5-CK-induced antinociception was not reversed by the opioid antagonist naloxone. Topological descriptors (fingerprints) were employed to narrow the antagonist selection to further investigate 5-CK’s mechanism of action. Next, based on the results of fingerprints analysis, functional antagonist assays were conducted on nociceptive tests. The effect of 5-CK was completely reversed in both cold plate and tail-flick tests by GABAA receptor antagonist bicuculline, but not by atropine or glibenclamide. Molecular docking studies suggest that 5-CK binds to the orthosteric binding site, with a similar binding profile to that observed for bicuculline and GABA. These results evidence that 5-CK has a centrally mediated antinociceptive effect, probably involving the activation of GABAergic pathways.

Highlights

Pain is a symptom associated with a variety of pathological states, frequently it is the first or the most important manifestation of a disease
In the early phase of the test, the pretreatment with 5-O-methylcneorumchromone K (5-CK) at 50 and 12.5 mg/Kg diminished the nociception caused by formalin (p < 0.05), indicating a potential analgesic activity
We demonstrate that 5-CK has intrinsic analgesic properties, not directly linked to the control of inflammation, and which involves the participation of the central nervous system probably mediated by GABAA receptors

Summary

Introduction

Pain is a symptom associated with a variety of pathological states, frequently it is the first or the most important manifestation of a disease. Sometimes pain can turn into a disease itself. When pain exceeds its biological function of protection and becomes chronic it negatively impacts both day-to-day life and mental health [1,2]. The proper pharmacological control of pain is an unsolved challenge for patients and health care providers. The ongoing treatment is primarily based on the use of opioid analgesics and non-steroidal anti-inflammatory drugs (NSAID). Even though those pharmacological classes are among the most widely used medications, they still are ineffective or unsafe for some patients, especially for those who suffer from chronic pain [3,4]. There are few drug development efforts that focus on targeting novel pathophysiological mechanisms to supply the treatment of patients who do not respond to available drugs [5,6]

Results

Discussion

Conclusion