Document Type

Poster

Publication Date

2021

Abstract

Our prior work demonstrates that adult prenatal alcohol exposed (PAE) rats with minimal nerve injury develop allodynia (pathological light touch sensitivity) in concert with aberrant peripheral-spinal glial and immune activation. Nerve-injured PAE rats display heightened proinflammatory cytokine production (IL-1β, TNF-α, CCL2) typically produced following activation of innate immune receptors, TLR4 and Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes. This suggests that PAE-related adaptations prime peripheral macrophages and central nervous system (CNS) glia to over-respond to subtle challenges through exaggerated TLR4 and NLRP3 inflammasome reactivity. Interestingly, morphine, a standard opioid pain therapeutic, binds the μ-opioid receptor and also glial TLR4 leading to NLRP3 inflammasome activation. Therefore, we hypothesized that PAE primes immune cell reactivity through augmented TLR4 activation and downstream NLRP3-mediated proinflammatory cytokine release, which is exacerbated by exposure to morphine treatment. Thus, we predicted morphine paradoxically exacerbates allodynia following an adult-onset peripheral nerve injury only in PAE offspring. We confirm PAE is a risk factor for developing allodynia in mice with minor injury. Results show that following minor nerve injury, morphine treatment (10 mg/kg, 5 subsequent days) significantly prolongs allodynia in PAE mice, while Sac control mice spontaneously resolve sooner. Moreover, selectively blocking NLRP3 inflammasome activity using the inhibitor, MCC950 (i.v. 10 mg/kg) reversed the morphine-prolongation of allodynia observed in PAE mice. In vitro studies were designed to examine the TLR4-NLRP3-dependent enhanced reactivity of PAE immune cells to typical immune stimuli with/without morphine treatment. Data show morphine further enhances NLRP3 inflammasome activity, as measured by flow cytometric detection of intracellular levels of active Caspase-1 and IL-1β release (by ELISA) from PAE leukocytes. Together, these data provide evidence that PAE exaggerates morphine-induced immune activation via the TLR4-NLRP3 pathway and may be predictive of adverse responses to opioids as pain therapeutics for individuals with FASD.

Comments

Poster presented at the Brain & Behavioral Health Research Day 2021

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