Abstract
BACKGROUND AND OBJECTIVES: Opioids are drugs used to relieve pain, but may cause increased pain sensitivity, known as opioid-induced hyperalgesia, which adversely affects pain management. This study aimed to check if fentanyl, an opioid widely used in the clinical practice, produces hyperalgesia that can be attenuated by duloxetine, fluoxetine and pregabalin. METHODS: Thirty male Wistar rats were divided into six groups. The animals in group 1 received 1mL of 0.9% saline solution intraperitoneally (IP) and gavage; group 2 received fentanyl at a dose of 100µg.kg-1 IP and 0.9% saline solution per gavage; groups 3, 4 and 5 received fentanyl at the dose of 100µg.kg-1 IP, and gavage with duloxetine, 40mg.kg-1, fluoxetine, 40mg.kg-1 and pregabalin, 40mg.kg-1, respectively. Under general anesthesia with isoflurane, all animals were submitted to plantar surgical incision. The application of Von Frey filaments assessed hyperalgesia at the second hour, one, three, five and seven days after treatment. RESULTS: Two hours after the procedure, no differences were observed between G1 and G2, although G3, G4, and G5 showed less hyperalgesia. On day one and day three, a greater hyperalgesic effect was observed in G2 when compared to G1, G3, G4 and G5. On day five, there was a hyperalgesic effect on G2, and on day seven, there were no differences among the groups. CONCLUSION: The results suggest that fentanyl induces hyperalgesia and the efficacy of duloxetine, fluoxetine, and pregabalin in reducing it.
Highlights
Pain is one of the most important and complex human experiences, associated with actual or potential tissue damage, and its treatment with opioids has increased substantially in recent years, making it’s prescription common in the United States[1,2]
Studies in rodents have demonstrated that fentanyl cause opioid-induced hyperalgesia (OIH) and suggested that the protein kinase Iiα (CaMKIIα) dependent of Ca2+/calmodulin in the lateral capsular division of the central nucleus of the amygdala (CeLC) and the spinal cord can play a key role in the modulation of the OIH12,13
The involvement of glutamate neurotransmission in synaptic plasticity suggests that pregabalin may be useful in attenuating OIH18, being a GABA analog drug, which selectively binds with high affinity to the calcium channels, widely distributed in the central nervous system (CNS) and peripheral, producing a modulating effect with a reduction of the excessive release of several excitatory neurotransmitters
Summary
Pain is one of the most important and complex human experiences, associated with actual or potential tissue damage, and its treatment with opioids has increased substantially in recent years, making it’s prescription common in the United States[1,2]. The increased release of glutamate in the dorsal horn of the spinal cord and the consequent sustained increase in stimulus and response of NMDA receptors by removal of magnesium mediated by protein kinase-C seem to be important mechanisms involved in OIH7 These NMDA receptors can be activated by opioids, which act as excitatory neurotransmitters facilitating calcium intake into the cell and central sensitization (CS). Regardless of anxiety or depression symptoms, suggesting that the pain reduction caused by pregabalin results mainly from the direct effect of the treatment, and not the indirect effect from the improvement of anxiety and depression symptoms[20] Behavioral tests such as the application of von Frey filaments and thermal hyperalgesia have been used to evaluate hyperalgesia in rats[21]. CONCLUSION: The results suggest that fentanyl induces hyperalgesia and the efficacy of duloxetine, fluoxetine, and pregabalin in reducing it
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