Saccharin and naltrexone prevent increased pain sensitivity and impaired long-term memory induced by repetitive neonatal noxious stimulation: role of BDNF and enkephalin

Abstract

This study aim to examine the hypothesis that repetitive painful stimuli during infancy will alter pain sensitivity and impair learning and memory during adulthood and that saccharin will prevent this through its analgesic effect. Naltrexone is used to examine if saccharin effect is mediated via the endogenous opioid system. Pain in rat pups was induced via needle pricks of the paws on day 1 of their birth (P0). All treatments/ manipulations started on day 1 and continued for 2 weeks. The radial arm water maze (RAWM) test was used to assess learning and memory. Pain threshold through foot-withdrawal response to a hot plate was also assessed. At the end of behavioral tests, animals were killed, hippocampus was dissected, and hippocampal levels of β-endorphin, enkephalin, and brain-derived neurotropic factor (BDNF) were assessed using ELISA. Naltrexone and saccharin combined normalized noxious stimulation induced increased pain sensitivity later in life. Furthermore, naltrexone and saccharin together mitigated the deficiency in learning and memory induced by noxious stimulation. Saccharin treatment prevented reduction in hippocampal enkephalin. Additionally, saccharin prevented hippocampal noxious stimulation induced BDNF decrement. Saccharin prevented long-term memory impairment during adulthood induced by repeated neonatal pain via mechanisms that appear to involve BDNF. Interestingly, naltrexone did not antagonize the effects of saccharin, instead naltrexone augmented saccharin effects.

Keywords: Cognition; Hippocampus; Learning; Neonates; Saccharin.