A Monoclonal Antibody against 6-Acetylmorphine Protects Female Mice Offspring from Adverse Behavioral Effects Induced by Prenatal Heroin Exposure

Abstract

Escalating opioid use among fertile women has increased the number of children being exposed to opioids during fetal life. Furthermore, accumulating evidence links prenatal opioid exposure, including opioid maintenance treatment, to longterm negative effects on cognition and behavior, and presses the need to explore novel treatment strategies for pregnant opioid users. The present study examined the potential of a monoclonal antibody (mAb) targeting heroin's first metabolite, 6-acetylmorphine (6-AM), in providing fetal protection against harmful effects of prenatal heroin exposure in mice. First, we examined anti-6-AM mAb's ability to block materno-fetal transfer of active metabolites after maternal heroin administration. Next, we studied whether maternal mAb pretreatment could prevent adverse effects in neonatal and adolescent offspring exposed to intrauterine heroin (3 Â 1.05 mg/kg). Anti-6-AM mAb pretreatment of pregnant dams profoundly reduced the distribution of active heroin metabolites to the fetal brain. Furthermore, maternal mAb administration prevented hyperactivity and drug sensitization in adolescent female offspring prenatally exposed to heroin. Our findings demonstrate that passive immunization with a 6-AM-specific antibody during pregnancy provides fetal neuroprotection against heroin metabolites, and thereby prevents persistent adverse behavioral effects in the offspring. An immunotherapeutic approach to protect the fetus against long-term effects of prenatal drug exposure has not been reported previously, and should be further explored as prophylactic treatment of pregnant heroin users susceptible to relapse.

Opioid receptor‐mediated changes in the NMDA receptor in developing rat and chicken

“…Cerebella from opioid exposed chicken were homogenised in ice‐cold 0.32 M sucrose. Binding studies were performed as previously described (Kvello et al, 2019). In short, samples were pre‐incubated in Tris−HCl buffer (pH 7.4, for 10 min in 25 °C) before the addition of 4 nM [ 3 H]‐ifenprodil (60 minutes, 25 °C).…”

Structural analysis of free and liganded forms of the Fab fragment of a high-affinity anti-cocaine antibody, h2E2

“…Immunization protocols using hapten-carrier linked conjugates have enabled investigators to generate high- # 2019 International Union of Crystallography affinity antibodies that are specifically directed against nonimmunogenic compounds such as heroin, cocaine, nicotine and phencyclidine, the usage and abuse of which pose considerable individual as well as public health problems. These antibodies have the potential to be effective therapeutics in reducing abuse and relapse behaviors by sequestering the target drug in the plasma, thereby dramatically reducing drug distribution to the central nervous system and blunting neurological effects (Carrera et al, 1995(Carrera et al, , 2000(Carrera et al, , 2001Fox et al, 1996;Kvello et al, 2016;Cerny & Cerny, 2008;Kosten & Owens, 2005). Furthermore, the drug-binding Fab fragments or lower molecular weight scFv single-chain fragments derived from them, which have relatively fast elimination rates compared with intact antibodies, have the additional potential to be used as rescue treatment agents to assist detoxification in cases of acute overdoses of toxic drugs.…”

Prenatal Opioid Exposure Enhances Responsiveness to Future Drug Reward and Alters Sensitivity to Pain: A Review of Preclinical Models and Contributing Mechanisms

“…The majority of preclinical studies have utilized rodent models, with rats being far more common than mice, although a few groups have employed mouse models (Castellano and Ammassari-Teule, 1984;Mithbaokar et al, 2016;Kvello et al, 2019;Robinson et al, 2019;Alipio et al, 2020). Other animal models used sparingly include guinea pigs which have a placental structure more similar to humans and are born precocious (used by Olsen and colleagues (Nettleton et al, 2008;Wallisch et al, 2010)) and chickens which have long been a model system for examining embryological development (Schrott and Sparber, 2004;Lucas et al, 2010;Jiang et al, 2011;Wang et al, 2017).…”