Female rats express heroin-induced and -conditioned suppression of peripheral nitric oxide production in response to endotoxin challenge

Abstract

Opioids and opioid-conditioned stimuli (CS) negatively alter host immunity, impairing the response to pathogens during opioid use and following drug cessation. Using male rats, our laboratory has determined that heroin or heroin-CS exposure preceding a lipopolysaccharide (LPS) challenge markedly suppresses normal induction of peripheral pro-inflammatory biomarkers. Presently, it is unknown if these heroin-induced and -conditioned effects extend to the female immune response. To begin this venture, the current study tested the direct effects of heroin and heroin-CS on LPS-induced peripheral nitric oxide (NO) production in female rats. We focused investigations on peripheral NO as it is a critical pro-inflammatory molecule necessary for pathogen resistance. In Experiment 1, male and female Lewis rats were administered 0 (Saline), 1, or 3 mg/kg heroin subcutaneously (s.c). Sixty minutes later, animals were injected with LPS (1 mg/kg, s.c.). Spleen and plasma samples were collected 6 h later to examine NO production through inducible NO synthase (iNOS) expression and nitrate/nitrite concentration, respectively. In Experiment 2, female Lewis rats underwent five, 60-minute context conditioning sessions with heroin (1 mg/kg, s.c.) or saline. On test day, CS-exposed and control (home cage) animals were injected with LPS (1 mg/kg, s.c.). Tissue was collected 6 h later to examine splenic iNOS expression and plasma nitrate/nitrite concentration. Both heroin administration alone and exposure to heroin-CS suppressed LPS-induced indices of NO production in spleen and plasma. Our results are the first to indicate that, similar to males, female rats express heroin-induced and -conditioned immunomodulation to a LPS challenge.