In Utero Morphine Exposure Induces Hypertension And Opioid Receptor‐Mediated Angiotensin II Sensitization

Abstract

Opioid use disorder (OUD) is associated with nearly two‐fold increased risk of cardiovascular disease, metabolic syndrome and diabetes. OUD by pregnant women is an understudied area related to the opioid epidemic leading to increased incidence of neonatal abstinence syndrome (NAS) and neonatal opioid withdrawal syndrome (NOWS). There is an interaction between the Renin‐Angiotensin System (RAS) and the endogenous opioid system (EOS) commonly associated with the development of hypertension. This study tests the hypothesis that in utero opioid exposure induces hypertension and increases vascular reactivity to Angiotensin‐II (AngII) in the adult offspring. Sprague Dawley dams were treated with escalating doses of a mu‐opioid receptor agonist morphine (MOR, 5‐20mg/kg/day, s.c) or saline (VEH). Weight gain was not different between MOR and VEH‐exposed pregnant rats (F‐MOR 100.2±9.5 vs F‐VEH 95±10 g, n=4, p=NS). Additionally, litter size was not different (F‐MOR13.75±0.2 vs F‐VEH 12.25±1.8 pups, n=4, p=NS). However, MOR‐exposed females exhibited low birth weight (F‐MOR 5.6±0.2 vs F‐VEH 7.2±0.6 g, n=20‐22, p<0.05). Both MOR‐exposed male and female offspring weighed less at weaning compared to VEH‐exposed offspring (p<0.05). At 16 weeks on CHOW diet, only MOR‐exposed female offspring continue to weigh significantly less than VEH‐exposed offspring (F‐MOR 264.5±9.7 vs F‐VEH 306.5±14 g, n=14‐16, p<0.05). Furthermore, both MOR‐exposed male and female rats are hypertensive (M‐MOR 127±0.84 vs M‐VEH 110±1.45 mmHg, p<0.05; F‐MOR 115.2±0.49 vs F‐VEH 93.5±0.50 mmHg, p<0.05). MOR‐exposed offspring displayed exacerbated acute pressor response to Angiotensin II (AngII, 0.01‐1 ng/Kg, intraarterial), the effect was greater in MOR‐exposed males than in females. Additionally, MOR‐exposed females show impaired maximal relaxation in response to acetylcholine (Ach, 10‐5 to 10‐9 M, F‐MOR 22.2±6 vs F‐VEH 44.7±4 %, p<0.05) but not MOR‐exposed males. However, only MOR‐exposed males show exacerbated maximal AngII‐induced vasoconstriction (M‐MOR 49.4±4 vs M‐VEH 35.8±3.9 %, p<0.05), which was blunted by an opioid receptor antagonist preincubation (naloxone, 1mM, 10 min, M‐MOR=49.4±4 vs M‐MOR+NAL 34.1±2.2 % max constriction, p<0.05; M‐VEH=35.8±3.9 vs M‐VEH+NAL=45.7±4 % max constriction, p=NS). At 16 weeks on high fat diet (HFD, 60% kcal from fat), male MOR‐exposed offspring displayed weight gain in response to HFD (M‐MOR 556.4±27 vs M‐VEH 598.3±12.4 g, p=NS), while female MOR‐exposed offspring were resistant to show diet‐induced obesity (F‐MOR 295.1±13 vs F‐VEH 350.6±22 g, p<0.05). HFD impaired maximal relaxation in response to acetylcholine in VEH‐exposed females (F‐VEH 44.7±4 vs. F‐VEH+HF 19±5 %, p<0.05) and MOR‐exposed males relaxation (M‐MOR 49.4±4 vs M‐MOR+HF 31.2±3 %, p<0.05) but not VEH‐exposed males or MOR‐exposed females. Furthermore, circulating AngII was increased in MOR‐exposed males (p<0.05 vs VEH). Maternal MOR exposure increases the risk of outcomes linked to cardiovascular and metabolic disease in adult offspring. The effects appeared to be mediated through a sex‐specific mechanism in hypertension development involving potential crosstalk between AngII and the EOS.