Prenatal alcohol exposure promotes NLRP3 inflammasome‐dependent immune actions following morphine treatment and paradoxically prolongs nerve injury‐induced pathological pain in female mice

Abstract

BackgroundNeuroimmune 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 proinflammatory cytokine IL‐1β release leading to neuropathic pain (allodynia) from minor nerve injury. While morphine acts on μ‐opioid receptors, it also activates immune receptors, TLR4, and NLRP3 inflammasome inducing IL‐1β. We hypothesized that PAE induces NLRP3 sensitization from morphine following nerve injury in adult mice.MethodsUtilizing a previously established moderate PAE paradigm, adult PAE and non‐PAE control female mice were exposed to a minor sciatic nerve injury and 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 NLRP3 inhibitor, MCC950 during chronic allodynia were examined. 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.ResultsFollowing minor nerve injury, mice with PAE developed a robust allodynia. Blocking NLRP3 activation fully reversed allodynia in both control and PAE mice. While morphine paradoxically prolonged allodynia only in PAE mice, minor nerve‐injured control mice remained stably non‐allodynic. Allodynia from nerve‐injured PAE without morphine spontaneously resolved much sooner. MCC950 treatment significantly shortened allodynia in morphine‐treated PAE mice. Morphine potentiated IL‐1β release from TLR4‐activated PAE immune cells and MCC950 treatment greatly reduced IL‐1β release.ConclusionsThese results indicate that in females, PAE prolongs allodynia following morphine treatment through NLRP3 activation. TLR4‐activated PAE immune cells demonstrated enhanced IL‐1β release with morphine via NLRP3 actions. Future studies are needed to address the adverse impact of morphine in males with PAE. These results are predictive of adverse opioid pain‐therapeutic responses in individuals with FASD.