The citrus flavanone naringenin prevents the development of morphine analgesic tolerance and conditioned place preference in male rats

Background Opioids are effective analgesics in the management of chronic pain. However, their clinical use is hindered by adverse side effects such as addiction and analgesic tolerance. Naringenin is a common polyphenolic constituent of the citrus fruits and is one of the most commonly consumed flavonoids within our regular diet. However, its influences on opioid tolerance and addiction have not yet been clarified.Objectives To examine the effect of different doses of naringenin on analgesic tolerance, conditioned place preference and neuroinflammation in morphine-exposed rats.Methods Analgesic tolerance was induced by the injection of 10 mg/kg morphine twice daily for 8 days in 70 male Wistar rats. To evaluate the effect of naringenin on the development of morphine tolerance, different doses (10, 25 and 50 mg/kg i.p.) were injected 15 min before morphine. The tail-flick test was used to assess nociceptive threshold. Conditioned place preference test was used to evaluate morphine-seeking behaviors. The lumbar spinal cord was assayed to determine glial fibrillary acidic protein (GFAP) and cyclooxygenase-2 (COX-2) levels by Western blotting.Results The data showed that naringenin could significantly prevent morphine tolerance (p < .001) and conditioned place preference. In addition, chronic morphine-induced GFAP and COX-2 overexpression was significantly reversed by 50 mg/kg naringenin (p < .05 and p < .01, respectively).Conclusion Our results suggest that naringenin may have a potential anti-tolerant/anti-addiction property against chronic morphine misuse and that this preventive effect is associated with its anti-neuroinflammatory effects.