RESUMO
BACKGROUND: Neuroimmune dysregulation from prenatal alcohol exposure (PAE) may contribute to neurological deficits associated with fetal alcohol spectrum disorders (FASD). PAE is a risk factor for developing peripheral immune and spinal glial sensitization and release of the proinflammatory cytokine IL-1ß, which lead to neuropathic pain (allodynia) from minor nerve injury. Although morphine acts on µ-opioid receptors, it also activates immune receptors, TLR4, and the NLRP3 inflammasome that induces IL-1ß. We hypothesized that PAE induces NLRP3 sensitization by morphine following nerve injury in adult mice. METHODS: We used an established moderate PAE paradigm, in which adult PAE and non-PAE control female mice were exposed to a minor sciatic nerve injury, and subsequent allodynia was measured using the von Frey fiber test. In control mice with standard sciatic damage or PAE mice with minor sciatic damage, the effects of the NLRP3 inhibitor, MCC950, were examined during chronic allodynia. Additionally, minor nerve-injured mice were treated with morphine, with or without MCC950. In vitro studies examined the TLR4-NLRP3-dependent proinflammatory response of peripheral macrophages to morphine and/or lipopolysaccharide, with or without MCC950. RESULTS: Mice with standard sciatic damage or PAE mice with minor sciatic damage developed robust allodynia. Blocking NLRP3 activation fully reversed allodynia in both control and PAE mice. Morphine paradoxically prolonged allodynia in PAE mice, while control mice with minor nerve injury remained stably non-allodynic. Allodynia resolved sooner in nerve-injured PAE mice without morphine treatment than in morphine-treated mice. MCC950 treatment significantly shortened allodynia in morphine-treated PAE mice. Morphine potentiated IL-1ß release from TLR4-activated PAE immune cells, while MCC950 treatment greatly reduced it. CONCLUSIONS: In female mice, PAE prolongs allodynia following morphine treatment through NLRP3 activation. TLR4-activated PAE immune cells showed enhanced IL-1ß release with morphine via NLRP3 actions. Similar studies are needed to examine the adverse impact of morphine in males with PAE. These results are predictive of adverse responses to opioid pain therapeutics in individuals with FASD.
RESUMO
Obstructive sleep apnea is characterized by recurrent episodes of pharyngeal collapse during sleep, resulting in intermittent hypoxia (IH), and is associated with a high incidence of hypertension and accelerated renal failure. In rodents, endothelin (ET)-1 contributes to IH-induced hypertension, and ET-1 levels inversely correlate with glomerular filtration rate in patients with end-stage chronic kidney disease (CKD). Therefore, we hypothesized that a dual ET receptor antagonist, macitentan (Actelion Pharmaceuticals), will attenuate and reverse hypertension and renal dysfunction in a rat model of combined IH and CKD. Male Sprague-Dawley rats received one of three diets (control, 0.2% adenine, and 0.2% adenine + 30 mg·kg-1·day-1 macitentan) for 2 wk followed by 2 wk of recovery diet. Rats were then exposed for 4 wk to air or IH (20 short exposures/h to 5% O2-5% CO2 7 h/day during sleep). Macitentan prevented the increases in mean arterial blood pressure caused by CKD, IH, and the combination of CKD + IH. However, macitentan did not improve kidney function, fibrosis, and inflammation. After CKD was established, rats were exposed to air or IH for 2 wk, and macitentan feeding continued for 2 more wk. Macitentan reversed the hypertension in IH, CKD, and CKD + IH groups without improving renal function. Our data suggest that macitentan could be an effective antihypertensive in patients with CKD and irreversible kidney damage as a way to protect the heart, brain, and eyes from elevated arterial pressure, but it does not reverse toxin-induced tubule atrophy.
