426 - Restoration of the Hypoxic Ventilatory Response by the Microglia Inhibitor Ibudilast in a Rat Model of Neonatal Opioid Withdrawal Syndrome

Poster Number: 426
Publication Number: 426.136

Allison Osborne, UH Rainbow Babies & Children's Hospital, Cleveland Heights, OH, United States; Catherine Mayer, Case Western Reserve University School of Medicine, Cleveland, OH, United States; Rachel Hyzny, Case Western Reserve University, Cleveland, OH, United States; Juliann Di Fiore, Case Western Reserve University, Cleveland, OH, United States; Stephen J. Lewis, Case Western Reserve University, Ceveand, OH, United States; Thomas M. Raffay, UH Rainbow Babies & Children's Hospital, Cleveland, OH, United States; Richard Martin, Case Western Reserve University School of Medicine, Lyndhurst, OH, United States; Peter MacFarlane, Rainbow Babies & Children’s Hospital/ Case Western Reserve University, Cleveland, OH, United States

Background: Infants born with neonatal opioid withdrawal syndrome (NOWS) display abnormal respiratory patterns including impaired ventilatory responses to hypoxia and hypercarbia challenges. These respiratory impairments were associated with increased microglia expression in key brainstem respiratory control regions. The microglia inhibitor ibudilast has been tested to treat symptoms of opioid withdrawal in adults.

Objective: Use a rat model of NOWS consisting of pre- and post-natal morphine exposure to assess whether postnatal ibudilast administration restores the acute hypoxic ventilatory response (HVR) and hypercapnic ventilatory response (HCVR).

Design/Methods: Pregnant female rats (dams) received twice-daily subcutaneous injections of morphine (5mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. After birth, the male pups received once-daily subcutaneous injections of morphine (5mg/kg), through postnatal day 10 to simulate postnatal morphine therapy. Experimental litters also received daily postnatal injections of ibudilast (5mg/kg) concurrent with morphine. Whole-body plethysmography was used precisely 24 hours later (P11) to assess ventilatory defense responses to acute hypoxia (HVR) and hypercapnia (HCVR) challenge (5 minutes at 10% O2 and 5% CO2, respectively).

Results: Pre/postnatal morphine exposure attenuated the HVR (59% above baseline) compared to saline treated rats (81% above baseline). The HCVR was also attenuated in morphine treated rats (25% above baseline) compared to saline (76% above baseline). Postnatal ibudilast treatment restored the HVR (82% above baseline) in morphine-exposed animals (Figure 1), but not the HCVR (35% above baseline).Conclusion(s): Postnatal ibudilast treatment may represent a promising therapy to minimize respiratory control dysfunction in NOWS infants. Given the brainstem gliosis and respiratory control dysfunction associated with SIDS, these data might also have implications for understanding the risk of SIDS associated with NOWS.
Effects of postnatal ibudilast administration on the hypoxic and hypercapnic ventilatory response in a rat model of NOWS(A) hypoxic (HVR; 10% O2, 5 min) and (B) hypercapnic ventilatory (HCVR; 5% CO2, 5 min) response of P11 day old male rat pups who received pre/postnatal morphine exposure (ie. NOWS model) and with (open triangles) or without (closed triangles) postnatal ibudilast (5mg/kg/day). NOWS model consisted of pups who received postnatal morphine (5mg/kg/day) following prenatal (5mg/kg, twice daily) morphine administration (3rd trimester). Control rats received pre/postnatal saline (closed circles). Note, morphine exposure attenuated the HVR (A) and HCVR (B), but only the HVR was restored by ibudilast. Data are expressed as % change in minute ventilation from baseline. *statistical difference from saline group for a given time point, p < 0.05.