Dextromethorphan attenuated the higher vulnerability to inflammatory thermal hyperalgesia caused by prenatal morphine exposure in rat offspring

Abstract

BackgroundCo-administration of dextromethorphan (DM) with morphine during pregnancy and throughout lactation has been found to reduce morphine physical dependence and tolerance in rat offspring. No evidence was presented, however, for the effect of DM co-administered with morphine during pregnancy on inflammatory hyperalgesia in morphine-exposed offspring. Therefore, we attempt to investigate the possible effect of prenatal morphine exposure on the vulnerability to hyperalgesia and the possible therapeutic effect of DM in the present study.MethodsFifty μl of carrageenan (20 mg/ml) was injected subcutaneously into the plantar surface of the right hind paw in p18 rats to induce hyperalgesia. Mean paw withdrawal latency was measured in the plantar test to index the severity of hyperalgesia. Using Western blotting and RT-PCR, the quantitative analyses of NMDA receptor NR1 and NR2B subunits were performed in spinal cords from different groups of animals.ResultsIn the carrageenan-induced hyperalgesia model, rat offspring passively exposed to morphine developed a severe hyperalgesia on postnatal day 18 (p18), which also had a more rapid time course than those in the controls. Co-administration of DM with morphine in the dams prevented this adverse effect of morphine in the offspring rats. Western blot and RT-PCR analysis showed that the levels of protein and mRNA of NMDA receptor NR1 and NR2B subunits were significantly higher in the lumbar spinal cords of rats (p14) exposed to prenatal morphine; the co-administration of DM could reverse the effect of morphine on NR1 and attenuate the effect on NR2B.ConclusionsThus, DM may have a great potential in the prevention of higher vulnerability to inflammatory thermal hyperalgesia in the offspring of morphine-addicted mothers.

Beneficial effects of co-treatment with dextromethorphan on prenatally methadone-exposed offspring

“…The goal of this study is to evaluate the effects of co-administration of DM with methadone in the prenatal stage on offspring [ 21 , 29 , 31 ]. The doses we used are within the clinical therapeutic ranges converted to rats based on the body surface area.…”

“…Studies have shown that DM reduced morphine reward as measured by CPP test, and this might be related to DM’s antagonizing effect on NMDA receptors that are involved in the activation of mesocorticolimbic dopaminergic systems [ 25 , 26 ]. Our previous studies also demonstrated that co-administration of DM with morphine during pregnancy and throughout lactation reduced several morphine-induced adverse effects [ 27 , 28 ] and could prevent higher vulnerability to inflammatory thermal hyperalgesia in rat offspring [ 29 ].…”

The cellular basis of fetal endoplasmic reticulum stress and oxidative stress in drug-induced neurodevelopmental deficits

“…Treatments with platelet derived growth factor (PDGF) ameliorated morphine-induced ROS productions and restored spine densities ( Cai et al, 2016 ). Furthermore, dextromethorphan, an active ingredient found in cough syrup, may be repurposed as a mitigator of adverse opioid effects during gestation and lactation periods since co-administration of dextromethophen with morphine were found to significantly attenuate morphine-induced neurologic effects ( Tao et al, 2011 ; Yang et al, 2006 ).…”

Morphine Perinatal Exposure Induces Long-Lasting Negative Emotional States in Adult Offspring Rodents

“…For instance, Tempel et al [20] described that prenatal exposure to morphine, at doses of 75 mg on gestation day (GD) 16, induces tolerance responses to analgesic effects in rats, through the downregulation of opioid receptors. In contrast, Tao et al [13] postulated that intrauterine morphine administration at a dose of 2 mg/kg alters pain threshold, inducing hyperalgesia, mainly in female rats.…”

“…Besides, the newborn can undergo neonatal abstinence syndrome (NAS) in the first days after birth. Characterized by negative symptoms related to the central nervous system (CNS), as well as respiratory and digestive systems dysfunction, it was observed in NAS sneezing, lacrimation, impaired sucking, reduced sleep duration, and irritability, which leads to physiological stress, requiring intensive care service, as well as contributing to low weight birth [8,12,13].…”