Preclinical Toxicity Screening of Intrathecal Oxytocin in Rats and Dogs

Abstract

Background Anatomic, physiologic, and behavioral studies in animals suggest that spinally released oxytocin should produce analgesia in humans and may also protect from chronic pain after injury. Here we report preclinical toxicity screening of oxytocin for intrathecal delivery. Methods Intrathecal oxytocin, 11 μg (6 IU) or vehicle, was injected intrathecally in 24 rats, followed by frequent behavioral assessment and histologic examination of spinal contents 2 or 14 days after injection. In 3 dogs, a range of intrathecal oxytocin doses (18-550 μg in 0.5 mL) was injected followed by physiologic, biochemical, and behavioral assessments. Ten dogs were then randomized to receive 5 daily injections of intrathecal oxytocin, 550 μg in 0.5 mL, or vehicle with similar assessments and, 2 days later, necropsy and histologic analysis. Results In rats intrathecal oxytocin resulted in transient scratching and itching behaviors, without other differences from vehicle. There was no behavioral, gross anatomic, or histologic evidence of neurotoxicity. Dose-ranging in dogs suggested mild effects on motor tone, blood pressure and heart rate at the 550 μg dose. Repeated boluses in dogs did not produce behavioral, biochemical, neurological, gross anatomic, or histologic evidence of neurotoxicity. Conclusions Substances, including natural neurotransmitters, may be toxic when administered in pharmacologic doses in the spinal cord. This preclinical toxicity screen in two species suggests that bolus injections of oxytocin in concentrations up to 1100 μg/mL is unlikely to cause neurotoxicity. They also support cautious clinical application of intrathecal oxytocin under regulatory supervision.

Oxytocin ameliorates the deleterious effect of pain in adult male rats

“…The significant increase in brain homogenate serotonin level in OXT subgroup (A) of the present study is in agreement with previous animal studies which suggested that serotonergic and oxytocinergic neurotransmission interact anatomically and functionally (Scantamburlo et al, 2009;Montag et al, 2011;Silva et al, 2013). Yaksh et al (2014) found that rats treated with oxytocin have an increased synthesis of 5-HT in the frontal cortex and brain stem. In addition, brain homogenate dopamine level was significantly increased which coincided with the study of Baskerville and Douglas (2010) who reported increase dopamine release in the ventral striatum and nucleus accumbens after oxytocin infusion in ventrotegmental dopaminergic neurons.…”

“…This excludes the cardiovascular complications, which goes in line with the previous study of Yang et al (2011b). However ABP and HR were significantly decreased after intravenous OXT administration and this coincided with the previous study of Yang et al( 2014) which demonstrated that intravenous OXT promoted a direct negative inotropic and chronotropic effects in rats (Yaksh et al, 2014). OXT acts on specific oxytocin atrial cardiomyocytic receptors, stimulate the release of acetylcholine, decreasing the rate and force of cardiac contraction (Montag et al, 2011) and, stimulates the release of atrial natriuretic peptide (ANP) which causes bradycardia, naturesis and hypotension (Ahmed et al, 2014).…”

Oxytocin-induced membrane hyperpolarization in pain-sensitive dorsal root ganglia neurons mediated by Ca2+/nNOS/NO/KATP pathway

“…Besides, intraperitoneal administration of synthetic OT causes a 40-fold increase in plasma OT levels (here >1500 pmol/L) in mice (Neumann et al, 2013). A preclinical toxicity screen suggests that plasma OT concentrations could be increased by 500 times from a baseline of approximately 100 to 50,000 pmol/L after intrathecal injections of OT (550 lg) without neurotoxicity in dogs (Yaksh et al, 2014). If plasma OT concentrations are increased by 500 times in rats, it will be close to the working concentration (10 À7 M) of OT in this study.…”

Phase 1 Safety Assessment of Intrathecal Oxytocin

“…12 Scratching behavior in rodents following intrathecal oxytocin is directed to the dermatomes near the injection site, consistent with a pruritic effect or, potentially hypesthesia. 14 This does not occur in dogs 13 and no subject in the current study reported itching or hypesthesia, so it is likely that there is a species dependent effect with rodents being susceptible.…”