MECANISMOS NEUROBIOLÓGICOSDA DEPENDÊNCIA DE OPIOIDES: O AGONISMO ENVIESADO COMO ESTRATÉGIA NO MANEJO SEGURO DA DOR CRÔNICA

Abstract

The treatment of moderate to severe chronic pain often requires the use of potent opioid analgesics, whose central pharmacological mechanism is based on the agonism of inhibitory G protein-coupled receptors, predominantly the mu-opioid receptor (MOR). However, the potent activation of these pathways induces tolerance and biological dependence, driving epidemiological crises of overdose and deaths on a global scale. The overall objective of this study was to analyze the neurobiological mechanisms of opioid analgesic dependence and examine the intracellular signaling pathways associated with drugs with high abuse potential, such as fentanyl, tramadol, and codeine, as well as pharmacotherapeutic alternatives in the prevention and/or reversal of TUO cases.The results indicated that highly lipophilic drugs, such as fentanyl, promote a marked cellular accumulation in the MOR receptor microenvironment, inducing broad patterns of intracellular phosphorylation and massive recruitment of beta-arrestin, which accelerates receptor desensitization. It is argued that the clinical management and mitigation of opioid use disorders (OUDs) depend both on adherence to the World Health Organization's analgesic ladder and the use of anti-inflammatory drugs, as well as on substitution therapies with buprenorphine or methadone. It is concluded that the future of safe chronic pain management and overcoming the impasse between analgesia and addiction lies in pharmacological innovation mediated by biased agonism, a strategy capable of isolating protective signaling via G protein and blocking beta-arrestin recruitment.