Gestational buprenorphine exposure: Effects on pregnancy, development, neonatal opioid withdrawal syndrome, and behavior in a translational rodent model.

BACKGROUND: The opioid crisis has led to an increased number of pregnant opioid-dependent women receiving opioid-maintenance therapy (e.g. buprenorphine, BUP), but little is known about the consequences of gestational BUP exposure on pregnancy outcomes, maternal care, or offspring development. METHODS: Our translational rodent model began BUP exposure to adult female rats (N = 30) at least 7 days before conception and continued throughout the postpartum period. Both therapeutic low-dose (BUP-LD, 0.3 mg/kg, s.c.) and overexposure high-dose (BUP-HD, 1.0 mg/kg) doses of BUP were compared to saline control. Female rats were bred in house with drug-naïve adult male rats. The day after parturition, litters were culled to 5 males/5 females and assigned randomly to various behavioral tests and assessed either neonates or adolescents. Litter characteristics, maternal caregiving, Neonatal Opioid Withdrawal Syndrome (NOWS), offspring development and adolescent behaviors were evaluated. RESULTS: BUP-LD decreased maternal care, delayed offspring development, decreased offspring body weight, length, temperature, and pain sensitivity (p's < .05). BUP-HD drastically reduced maternal care and offspring survival, altered litter characteristics, and increased NOWS (p's < .05). CONCLUSION: These results demonstrate that the therapeutic BUP-LD in rats was relatively safe with subtle effects on maternal care and rodent offspring. However, overexposure BUP-HD in rats produced NOWS and compromised maternal caregiving as well as rodent offspring survival. More research is critical to validate the translational implication of these findings for human opioid-dependent mothers maintained on BUP-maintenance therapy.

Effect of selective versus nonselective cyclooxygenase inhibitors on gastric ulceration scores and intestinal inflammation in horses.

OBJECTIVE: To determine whether a cyclooxygenase (COX)-2 selective nonsteroidal anti-inflammatory drug (NSAID) would reduce gastric ulceration and gastrointestinal (GI) inflammation compared with a non-COX selective NSAID. STUDY DESIGN: Randomized block design. ANIMALS: Twenty-five healthy adult horses. METHODS: Horses were randomly assigned to receive placebo (n = 5), phenylbutazone (n = 10), or firocoxib (n = 10) administered daily for 10 days. Gastroscopy was performed on days 0 and 10, and both squamous and glandular ulcers were scored according to established scoring criteria. Fecal samples were collected on days 0, 10, and 20 to test for fecal myeloperoxidase (MPO) concentration by enzyme-linked immunosorbent assay. RESULTS: Both classes of NSAID induced GI injury as determined by gastric ulceration scores and fecal MPO. Glandular gastric ulceration scores and fecal MPO concentrations were higher in horses treated with phenylbutazone at day 10 (P < .001 and P = .0018, respectively). Increases in fecal MPO were significantly decreased 10 days following cessation of treatment for firocoxib but remained greater than baseline for the phenylbutazone group. CONCLUSION: Although both classes of NSAID induced gastric ulceration, the COX-2 selective NSAID firocoxib induced less severe glandular ulceration. Although there were increases in fecal MPO in both groups after 10 days of treatment, this increase was significant only in horses receiving the nonselective COX inhibitor phenylbutazone. CLINICAL SIGNIFICANCE: These findings suggest that both classes of NSAID induce GI injury in horses; however, at the dosages used in this study, the COX-2 selective NSAID firocoxib resulted in less severe injury.

Differential effects of selective and non-selective cyclooxygenase inhibitors on fecal microbiota in adult horses.

Non-steroidal anti-inflammatory drugs (NSAIDs) are routinely used in both veterinary and human medicine. Gastrointestinal injury is a frequent adverse event associated with NSAID use and evidence suggests that NSAIDs induce gastrointestinal microbial imbalance (i.e., dysbiosis) in both animals and people. It is unknown, however, whether cyclooxygenase (COX)-2-selective NSAIDs induce dysbiosis, or if this phenomenon occurs in horses administered any class of NSAIDs. Therefore, our objectives were to determine whether the composition and diversity of the fecal microbiota of adult horses were altered by NSAID use, and whether these effects differed between non-selective and COX-2-selective NSAIDs. Twenty-five adult horses were randomly assigned to 1 of 3 groups: control (n = 5); phenylbutazone (n = 10); or, firocoxib (n = 10). Treatments were administered for 10 days. Fecal samples were collected every 5 days for 25 days. DNA was extracted from feces and the 16S rRNA gene amplified and sequenced to determine the composition of the microbiota and the inferred metagenome. While the fecal microbiota profile of the control group remained stable over time, the phenylbutazone and firocoxib groups had decreased diversity, and alteration of their microbiota profiles was most pronounced at day 10. Similarly, there were clear alterations of the inferred metagenome at day 10 compared to all other days, indicating that use of both non-selective and selective COX inhibitors resulted in temporary alterations of the fecal microbiota and inferred metagenome. Dysbiosis associated with NSAID administration is clinically relevant because dysbiosis has been associated with several important diseases of horses including abdominal pain (colic), colitis, enteric infections, and laminitis.