Contribution of Opioid and Nitrergic Systems to m-Trifluoromethyl diphenyl Diselenide Attenuates Morphine-Induced Tolerance in Mice

Abstract

m-Trifluoromethyl diphenyl diselenide (TFDD) has antinociceptive and antidepressant-like properties and attenuates morphine withdrawal signs in mice. This study investigated if TFDD affects the development of morphine tolerance to its antinociceptive and antidepressant-like effects in mice. We also investigated whether TFDD modulates signaling pathways related to morphine tolerance, including the opioid receptors and some parameters of the nitrergic system. Male adult Swiss mice received morphine alone (5 mg/ kg, subcutaneous) and in combination with TFDD (10 mg/kg, intragastric) for 7 days. Mice were subjected to hot plate and forced swim tests on days 1, 3, 5, and 7 of the experimental protocol. Repeated TFDD administrations avoided tolerance development mediated by morphine, including its antinociceptive and antidepressant-like effects. A single morphine dose increased MOR and NOx but decreased iNOS contents in the mouse cerebral cortex. In turn, single morphine and TFDD co-administration restored the MOR and iNOS protein levels. On the other hand, morphine repeated doses enhanced DOR and reduced MOR and NOx contents, whereas the morphine and TFDD association reestablished DOR and NOx levels in the mouse cerebral cortex. In conclusion, some opioid and nitrergic system parameters might contribute to TFDD attenuation of antinociceptive and antidepressant-like tolerance induced by morphine in mice.

Recent Progress in Synthetic and Biological Application of Diorganyl Diselenides

“…[301] m-Trifluoromethyl diphenyl diselenide has demonstrated effectiveness in mitigating morphine-induced antinociceptive and antidepressant-like tolerance in mice by modulating the opioid and nitrergic systems. [299] Additionally, it has shown efficacy in abolishing hyperlocomotion, as reported by Rodrigues et al [302] Moreover, m-trifluoromethyl diphenyl diselenide has exhibited protective effects against oxidative stress-induced hepatic, renal, and hippocampal toxicity in mice exposed to morphine. [303] Diselenide-based nanoformulations and prodrugs have emerged as promising strategies for alleviating inflammation, demonstrating efficacy across various experimental models.…”

“…m‐Trifluoromethyl diphenyl diselenide has demonstrated effectiveness in mitigating morphine‐induced antinociceptive and antidepressant‐like tolerance in mice by modulating the opioid and nitrergic systems [299] . Additionally, it has shown efficacy in abolishing hyperlocomotion, as reported by Rodrigues et al [302] .…”

“…[298] In experimental models exploring the pain-depression dyad, m-trifluoromethyl diphenyl diselenide has been shown to have antinociceptive and antidepressant-like properties in mice. [299,300] Morphine, a potent opioid drug extensively prescribed for pain management, may lead to tolerance and hyperalgesia with prolonged use in individuals experiencing persistent or chronic pain. [301] m-Trifluoromethyl diphenyl diselenide has demonstrated effectiveness in mitigating morphine-induced antinociceptive and antidepressant-like tolerance in mice by modulating the opioid and nitrergic systems.…”

“…In experimental models exploring the pain‐depression dyad, m‐trifluoromethyl diphenyl diselenide has been shown to have antinociceptive and antidepressant‐like properties in mice [299,300] …”